MAD2L1
EXTENDED 220 aa (canonical 205 aa) · UniProt Q13257 · CDLMPS
chr4:120066779:-:CTG:ENST00000296509.11
AI summary N-terminal extension adds a folded helix predicted by SignalP/TargetP to act as a cleavable signal peptide, absent from canonical MAD2L1.
How it diverges
The added 15-aa N-terminus forms a confidently-folded helix (pLDDT ~0.86) that both SignalP and TargetP independently call a genuine signal peptide with a defined cleavage site — a targeting feature the canonical protein, which lacks any such signal, does not have. DeepLoc's top-class call stays 'Cytoplasm' for both forms but with reduced confidence and a new peripheral-membrane association for the isoform, consistent with the new signal peptide perturbing the classifier rather than being noise. However, the extension helix shows very high PAE relative to the shared body (~24 Å) and almost no contacts with the core, so it reads as a confidently-folded but structurally unanchored appendage rather than one integrated into the checkpoint fold.
Why it matters
MAD2L1 is a nuclear/nuclear-envelope checkpoint protein that must reach kinetochores and the MAD1 leucine-zipper interface to enforce the SAC; a genuine, cleavable N-terminal signal peptide would be functionally incompatible with this known localization and could reroute the extended isoform toward the secretory pathway instead of nuclear pores/kinetochores, potentially producing a pool of MAD2L1 unable to participate in checkpoint signaling. Because the shared HORMA-domain core and MAD1-binding surface are structurally unaffected (no domain loss, and the extension is not docked onto the body), any functional consequence would act through mislocalization/sequestration rather than through altering the checkpoint-binding fold itself.
LLM confidence low
DeepLoc's canonical prediction (Cytoplasm) does not match the known nuclear/nuclear-envelope localization, so the localization tool is miscalibrated for this protein; the SignalP/TargetP signal-peptide call is intriguing but cannot be confirmed as a real localization conflict under the calibration rule, and the extension's high PAE to the core body means its structural integration (and thus its biological plausibility as a functional signal) is unresolved.
Folding
Canonical (205 aa)
Download CIF
Isoform (220 aa)
Download CIF
Coloured by ESMFold2 pLDDT confidence (blue = high, orange/red = low).
Differential region — residues 1–15 (added in isoform) — recoloured on a yellow→purple pLDDT ramp so it stands out.
Drag to rotate · scroll to zoom · download a CIF to explore in your own viewer.
Canonical PAE
Isoform PAE
Predicted aligned error: expected Cα error (Å) at residue j when the fold is superposed on residue i. Dark = confident relative placement; bright = uncertain.
The dashed outline marks the differential region (1–15).
Evidence — click any tile for the differential-region detail
C
Conservation
Not interesting
LLM reasoning
The N-terminal extension added by this isoform shows no evidence of purifying selection at the protein level: primate amino-acid identity is 75.2% versus 99.7% for the canonical sequence over the same species set, mammalian identity drops further to 45.8% versus 95.4% canonical, and absolute phyloP over the unique region is only -0.28 (well below the ~2 threshold for constraint), in sharp contrast to the shared/canonical region's phyloP of 4.26. This pattern — low cross-species identity relative to the canonical baseline and near-zero phyloP — is consistent with the extension deriving from sequence that was not historically coding (as expected for an extension drawing on former 5'UTR/intronic sequence) rather than a conserved functional element. Frac_intact values are not comparable between the short unique span and the longer canonical span and are not used to weigh this call.
Unique region 75.2% similar across primates
How well is the isoform-unique region conserved at the amino-acid level across primates (mean percent identity)? High AA identity in close relatives argues the alternative protein is real and translated, not a sequencing or annotation artifact. (Reading-frame intactness is shown as context.)
Comparison
Sequence conservation · primate
mean AA identity over the differential ORF is the score basis; frame intactness across the clade is context
| Conservation metric | Canonical ORF | Differential ORF |
|---|---|---|
| Mean AA identity | 100% | 75% |
| Frame intact (fraction of species) | 96% | 88% |
| Species aligned | 25 | 25 |
| Species frame-intact | 24 | 22 |
| Start codon conserved | 100% | 96% |
| Deepest intact species | Microcebus_murinus | Microcebus_murinus |
| Phylo depth (MRCA) | 7 | 7 |
Unique region 45.8% similar across mammals
The same amino-acid identity test across mammals. Conservation over deeper evolutionary distance is stronger evidence the ORF is under selection to be translated. (Reading-frame intactness is shown as context.)
Comparison
Sequence conservation · mammalian
mean AA identity over the differential ORF is the score basis; frame intactness across the clade is context
| Conservation metric | Canonical ORF | Differential ORF |
|---|---|---|
| Mean AA identity | 95% | 46% |
| Frame intact (fraction of species) | 35% | 20% |
| Species aligned | 20 | 20 |
| Species frame-intact | 7 | 4 |
| Start codon conserved | 95% | 64% |
| Deepest intact species | Loxodonta_africana | Microcebus_murinus |
| Phylo depth (MRCA) | 12 | 7 |
Unique region PhyloP: -0.28 — neutral selection
phyloP / phastCons measure per-base evolutionary constraint. A high absolute phyloP over the differential region means the sequence itself is under strong purifying selection — evidence it is coding and does something. (Enrichment over the shared core is shown as context only.)
Comparison
Per-base conservation · differential region
absolute mean phyloP over the differential region is the score basis (high = strong purifying selection); the shared column and enrichment are context, not the claim
| Track | Differential | Shared | vs shared |
|---|---|---|---|
| phyloP mean | -0.284 | 4.26 | -0.0668 |
| phastCons mean | 0.0496 | 0.887 | — |
Start site · canonical vs isoform
initiation context + per-base conservation at each start codon
| Property | Canonical | Isoform |
|---|---|---|
| Start codon | ATG | CTG |
| Kozak context (−9..+4) | TCCCTGGCCATGG | CTGTGGTTGCTGT |
| phyloP at start codon | 6.88 | -0.529 |
| phastCons at start codon | 1 | 0 |
| phyloP over Kozak window | 2.69 | -0.315 |
| phastCons over Kozak window | 0.479 | 0 |
| Kozak mismatch — full consensus | 4 | 11 |
| Kozak window GC content | 0.692 | 0.538 |
D
Detection
Interesting
LLM reasoning
This N-terminal extension has direct peptide-level proof: two isoform-unique peptides spanning the added MSAEWKRVLLFVSLA sequence were PepQuery2-validated (best hyperscore 24.8, p as low as 1e-4), confirming the extended start site is actually translated into protein, not just a transcriptional artifact. Ribosome-profiling support is real but modest and narrow: the alt TIS is significantly initiated only in HeLa (p=0.0061), with no data available in the other five cell lines, so breadth of detection is unconfirmed rather than negative. Initiation efficiency there is genuine but low relative to the canonical start in the same cell line (0.061 vs 1.50, roughly 4% of canonical usage), consistent with a minor upstream start that is nonetheless clearly used and clearly translated. Taken together, the mass-spec confirmation is the strongest and most decisive piece of evidence here, backed by a significant if single-line Ribo-seq signal.
detected in 1/6 cell lines
Is the alternative start used in more than one cell line? Reproducible initiation across independent samples argues against a one-off ribosome artifact.
Comparison
Per-cell-line usage · canonical vs isoform
Fisher q = 0.00613
| Cell line | Canonical | Isoform | p-value |
|---|---|---|---|
| HeLa | 62.7 | 2.55 | 0.00613 |
| K562 | 20.5 | — | — |
| U2OS | 11 | — | — |
alt used 0.041× vs canonical
How efficiently ribosomes initiate at this start (TIS) relative to background, per cell line. Strong, reproducible initiation supports a genuine translation event.
Comparison
Start-Site Usage · canonical vs isoform
ribosome initiation efficiency at the canonical start vs this alternative start, per cell line
| Cell line | Canonical | Isoform |
|---|---|---|
| HeLa | 1.5 | 0.0609 |
| K562 | 0.545 | — |
| U2OS | 0.174 | — |
2/5 isoform-unique peptides validated
Were tryptic peptides unique to the differential region detected by mass spec? Direct peptide evidence is the strongest proof the isoform protein exists.
Comparison
Peptide Evidence (canonical vs isoform)
isoform-unique peptides are direct evidence the alternative protein exists
| Feature | Canonical | Isoform |
|---|---|---|
| Tryptic peptides (in-silico) | 34 | 5 |
| Validated by mass-spec | 0 | 2 |
| Isoform-unique peptides | — | 5 |
Details
Peptide Evidence (canonical vs isoform)
- peptide VLLFVSLAMALQLSR 7–22
- peptide MSAEWKR 0–7
- peptide SAEWKR 1–7
- validated RVLLFVSLAMALQLSR 6–22
- validated VLLFVSLAMALQLSREQGITLR 7–29
L
Localization
Interesting
LLM reasoning
The N-terminal extension introduces a predicted signal peptide that is entirely absent from the canonical protein: SignalP flips from OTHER to SP with a probability delta of 0.999 and a cleavage site at position 23-24 (Pr 0.91), and TargetP concurringly flips from noTP to SP (SP-probability delta +0.71), both driven by the added 15-aa N-terminal segment (MSAEWKRVLLFVSLA) ahead of the canonical start. This is consistent with the extension creating a genuine N-terminal targeting signal that the canonical MAD2L1 start site lacks, which would redirect the extended isoform toward the secretory pathway rather than staying purely cytoplasmic. The overall DeepLoc top-class call stays Cytoplasm for both forms and nuclear export signal is unchanged, but the isoform gains peripheral membrane association (canonical: Soluble; isoform: Peripheral|Soluble) and its top-class confidence drops from 0.66 to 0.52, indicating the classifier is less certain and sees membrane-associated character emerging — coherent with a new signal peptide being present. Taken together, two independent targeting predictors agreeing on a novel signal peptide is a strong, concordant signal that this extension is not neutral cargo but could redirect the protein's trafficking.
iso: Cytoplasm | canon: Cytoplasm
Do the predicted localization features (DeepLoc prediction, sorting signals, or membrane association) differ between the canonical and the isoform? A protein with changed localization features acts in a different cellular context.
Comparison
Subcellular localization (DeepLoc)
localization features changed (prediction/signals/membrane)
| Property | Canonical | Isoform |
|---|---|---|
| Predicted location | Cytoplasm | Cytoplasm |
| Sorting signals | Nuclear export signal | Nuclear export signal |
| Membrane | Soluble | Peripheral|Soluble |
iso: SP | canon: noTP
Do N-terminal targeting signals (SignalP secretion, TargetP mitochondrial/chloroplast) differ between canonical and isoform? N-terminal changes most directly add or remove targeting peptides.
M
Mutation Landscape
Not interesting
LLM reasoning
This is an N-terminal extension whose added 15 residues derive from sequence that was never coding — confirmed directly: all 41 variant records intersecting the unique region are annotated "intronic," consistent with the extension's unique region being former 5'UTR/intron rather than protein-coding sequence. The germline-constraint inputs are therefore uninterpretable by construction (gnomAD ratio and ESM-C reflect non-coding selection/composition, not protein tolerance), leaving disease-variant density as the only readable signal. That signal is quiet and points away from relevance: disease variants are depleted rather than enriched in the unique region (enrichment ratio 0.38, 3 unique vs 107 shared), there are zero pathogenic ClinVar calls in either region, and the histogram of all 18 ClinVar variants on this isoform shows every one falls in the shared canonical region (positions 21-219, isoform numbering) with none in the unique 1-15 stretch. No clustering, no pathogenic burden, and no informative constraint signal converge on a negative result.
gnomAD variants 1.84× more in unique region — tolerant
Does healthy human germline variation (gnomAD) avoid this region (depletion ratio < 1×), and is it intrinsically constrained (ESM-C constraint delta > 0)? Depletion of population variation plus high sequence constraint mean the region resists change — it is functionally important. Scored only where the unique region is canonical coding sequence, i.e. on truncations. gnomAD is a tolerance catalogue, not a disease one; disease/cancer variants (ClinVar / COSMIC) live in M2.
Comparison
Germline Variants · differential vs shared region
gnomAD (population) variant density per nucleotide — depletion ratio < 1× means healthy human variation avoids the region (constrained), the M1 basis alongside ESM-C constraint
| Variant set | Differential | Shared | Depletion ratio |
|---|---|---|---|
| gnomAD variants | 38 | 283 | 1.8× |
Sequence constraint (ESM-C) · differential vs shared region
lower LLR = more constrained; enrichment = differential / conserved
| Property | Differential | Shared | Enrichment |
|---|---|---|---|
| ESM-C mean LLR | -2.43 | -0.0474 | — |
| Constrained positions | 0 | 1 | — |
Predicted-damaging variants · germline (gnomAD)
AlphaMissense / ESM-C / LoF calls per region (length-normalized)
| Variant set | Differential | Shared | Enrichment |
|---|---|---|---|
| Scorable variants | 37 | 283 | 1.8× |
| Damaging variants | 3 | 144 | 0.28× |
| — of which loss-of-function | 3 | 14 | 2.9× |
| AlphaMissense-pathogenic | 0 | 83 | 0× |
Predictor scores · germline (gnomAD)
scored: 396 ESM-C · 254 AlphaMissense
| Property | Differential | Shared |
|---|---|---|
| Mean ΔLLR (ESM-C) | -0.172 | -5.78 |
| Min ΔLLR (ESM-C) | -1.86 | -14.1 |
| Mean AlphaMissense | — | 0.51 |
Disease variants 2.61× less in unique region — depleted
Are disease (ClinVar / COSMIC) variants enriched per nucleotide in the differential region versus the shared core (disease enrichment ratio ≥ 1×)? Disease variants concentrating in the unique region tie it to phenotype.
Comparison
Clinical-variant burden · differential vs shared region
counts per region; ratio is density-normalized (variants per nucleotide, differential ÷ shared — ≥1× = disease variants concentrate in the differential region, the M2 basis)
| Variant set | Differential | Shared | Enrichment |
|---|---|---|---|
| Disease variants | 3 | 107 | 0.38× |
| Pathogenic | 0 | 0 | — |
Predicted-damaging variants · disease (ClinVar/COSMIC)
AlphaMissense / ESM-C / LoF calls per region (length-normalized)
| Variant set | Differential | Shared | Enrichment |
|---|---|---|---|
| Scorable variants | 2 | 107 | 0.26× |
| Damaging variants | 0 | 68 | 0× |
| — of which loss-of-function | 0 | 16 | 0× |
| AlphaMissense-pathogenic | 0 | 37 | 0× |
Predictor scores · disease (ClinVar/COSMIC)
scored: 396 ESM-C · 254 AlphaMissense
| Property | Differential | Shared |
|---|---|---|
| Mean ΔLLR (ESM-C) | -0.602 | -7.05 |
| Min ΔLLR (ESM-C) | -0.609 | -13.4 |
| Mean AlphaMissense | — | 0.552 |
P
Predicted Structure
Neutral
LLM reasoning
The 18-residue extension helix (isoform residues 3-20) is genuinely folded, with pLDDT holding at 0.72-0.91 across most of its length before tapering to 0.64-0.66 at its C-terminal edge, so it is a real, confidently-modeled secondary-structure element rather than a coil artifact. However it is not docked against the core: PAE between the extension (1-20) and the rest of the protein (21-220) averages 23.6 Å despite the shared body being internally coherent (PAE 2.0 Å within itself), and direct contacts are minimal — only 6 contacts total, confined to the two residues immediately adjoining the extension (21-22) rather than spread over a genuine interface. The shared-region RMSD of 3.39 Å must also be discounted: canonical pTM is a strong 0.95 and shared pLDDT is high (~0.94), so confidence is not the caveat, but the extension's own PAE relative to the body shows its orientation is unresolved, meaning the 'refolding' reading is not supported by a stable relative placement. Net picture: a confidently-folded but structurally unanchored appendage, which does not rise to a clear functional structural signal.
pLDDT Differential Region:
0.856
Does the gained/lost region fold into ordered structure (pLDDT) and shift the protein's biophysical character (charge, hydropathy, disorder)? Structured, biophysically distinct regions are more likely to be functional.
Comparison
Structure (ESMFold2) · canonical vs isoform
TM-score 0.935 · RMSD 0.77 Å · 10 interface contacts
| Metric | Canonical | Isoform |
|---|---|---|
| pLDDT (whole protein) | 0.938 | 0.935 |
Fold confidence · differential vs shared region
mean ESMFold2 pLDDT in each region
| Metric | Differential | Shared | Enrichment |
|---|---|---|---|
| pLDDT | 0.856 | 0.853 | 1 |
Shared-Region RMSD:
3.39 Å
The shared region is the stretch of protein identical in both the isoform and the canonical (the canonical body for an extension; the post-truncation body for a truncation). Folded in both contexts it normally comes out nearly identical, so its Cα backbone RMSD ≈ 0. A high shared-region RMSD (superposed on the shared residues only, from the ESMFold2 structures) means the extension or truncation reorganizes how the retained region folds — a rare, high-interest functional signal. TM-score is a length-normalized companion; the check only fires when both structures are confidently folded, and uORF/altORF isoforms (no shared region) are not evaluable.
Comparison
Shared-region structural change
Cα RMSD superposed on the shared residues only; TM-score is length-normalized · shared-region Cα RMSD 3.39 Å · shared TM-score 0.968 · shared region 205 aa · min shared pLDDT 0.938 · global TM-score 0.935 · global RMSD 0.77 Å
| Property | Canonical | Isoform |
|---|---|---|
| Shared-region pLDDT | 0.938 | 0.941 |
1 secondary structure identified in unique region
Does the differential region contain actual secondary structure — a helix or strand — rather than coil? ESMFold2 predicts coordinates but no secondary structure, so elements are assigned from those coordinates (P-SEA, Cα geometry). Because they are derived from a prediction, each element carries its own mean pLDDT: a geometrically clean helix running through a disordered stretch is geometry fitted to a guess, so BOTH length and confidence are required to score. The direction differs by ORF type — an extension GAINS the element (a candidate functional addition), a truncation LOSES one, and there the element is read off the canonical structure because the removed segment exists only in it. This says nothing about whether the element is integrated with the rest of the fold; the contact and PAE evidence in this same category answers that.
Comparison
Secondary structure · differential vs shared region
helices and strands assigned from the predicted coordinates (P-SEA)
| Metric | Differential | Shared |
|---|---|---|
| Alpha helices | 1 | 3 |
| Beta strands | 0 | 5 |
| Longest element (aa) | 18 | 23 |
| Mean pLDDT | 0.82 | 0.97 |
Elements and coordinates
1 in the differential region, 8 in the shared core — residue numbering is 1-based on the protein holding the region
| Isoform-unique | Shared core |
|---|---|
| alpha helix 3–20 18 aa · pLDDT 0.82 | alpha helix 28–50 23 aa · pLDDT 0.97 |
| — | alpha helix 74–93 20 aa · pLDDT 0.96 |
| — | beta strand 98–104 7 aa · pLDDT 0.97 |
| — | beta strand 115–121 7 aa · pLDDT 0.98 |
| — | alpha helix 136–156 21 aa · pLDDT 0.95 |
| — | beta strand 163–171 9 aa · pLDDT 0.97 |
| — | beta strand 193–202 10 aa · pLDDT 0.96 |
| — | beta strand 206–215 10 aa · pLDDT 0.98 |
Below threshold
0 in the differential region, 3 in the shared core — shorter than 6 aa or below pLDDT 0.70, so not counted above
| Isoform-unique | Shared core |
|---|---|
| — | beta strand 58–62 5 aa · pLDDT 0.96 |
| — | beta strand 67–71 5 aa · pLDDT 0.97 |
| — | beta strand 182–185 4 aa · pLDDT 0.90 |
S
Structural Characteristics
Neutral
LLM reasoning
The 15-residue N-terminal extension added ahead of the canonical MAD2L1 start shows no strong structural signature: it does not overlap any real InterPro domain (the single hit in the differential region is the HORMA domain superfamily call, which spans into the shared region and reflects the retained canonical fold, not a new domain gained by the extension), and whole-protein hydropathy/charge/disorder shifts are all below threshold (gravy delta 0.07, fraction-charged delta -0.004, disorder delta -0.008), so the extension does not measurably alter the protein's bulk biophysical character despite the unique region itself being locally more hydrophobic and basic than the shared core. The sparse-autoencoder magnitude check does fire (strongest shared-feature activation shift 12.81 vs threshold 10.0), indicating the extension does perturb the ESM-C embedding space, but per instructions this is a presence/absence signal only, not corroborated by any domain or biophysical change, and gained/lost feature counts (67/12) are not informative on their own. Taken together, one lower-confidence embedding-level signal against two null structural/biophysical readouts nets to no clear, well-supported functional signal in this dimension.
No diverging domains
Does the isoform gain or lose a real InterPro functional domain in the differential region (disorder/structural-only signatures excluded)? Gaining or losing a domain changes function directly.
Comparison
Domains & motifs (canonical vs isoform)
gained = only in the isoform; lost = only in the canonical
| Feature | Canonical | Isoform |
|---|---|---|
| InterPro domains | 6 | 6 |
| Short linear motifs | 2 | 2 |
more hydrophobic (+1.03) · less charged (-0.06) · less disordered (-0.12)
Biophysical character of the isoform-differential region versus the shared canonical core — pI, hydropathy, charge, disorder and related properties. Descriptive; the folding (P1) score keys off the GRAVY / charge / disorder deltas.
Comparison
Biophysics · differential vs shared region
highlighted rows are enriched in the differential region
| Property | Differential | Shared | Enrichment |
|---|---|---|---|
| Isoelectric point (pI) | 10.1 | 4.69 | 2.16 |
| Hydropathy (GRAVY) | 0.913 | -0.12 | -7.58 |
| Fraction charged | 0.2 | 0.259 | 0.774 |
| Disorder fraction | -0.0596 | 0.0591 | -1.01 |
| Disorder-promoting | 0.467 | 0.493 | 0.947 |
| Low-complexity fraction | 0 | 0 | — |
| Prion-like fraction | 0.133 | 0.239 | 0.558 |
| LLPS score | 0.0584 | 0.143 | 0.408 |
| π–π propensity | 0.2 | 0.234 | 0.854 |
| Aromaticity | 0.133 | 0.0927 | 1.44 |
| Instability index | 50.3 | 51 | 0.987 |
| Shannon entropy | 3.19 | 4.06 | 0.785 |
| Normalized complexity | 0.817 | 0.94 | 0.869 |
79 SAE features differ
Sparse-autoencoder (SAE) interpretability features on the ESM-C residual stream, comparing the isoform against the canonical protein. This is the S3 criterion — a presence check that fires when any interpretable feature is gained or lost. Only the top 30 features per category (ranked by activation, prevalence ≥ 2) are saved; each table shows the top 10 interpretable features, and generic / "unknown" features are hidden unless you expand it. What are SAE features? →
Part 1 · Global feature comparison
Which SAE features fire in the isoform vs the canonical protein, across the whole sequence.
Isoform-only features — 67 total (prevalence ≥ 2)
| Feature | Label | Description | Activation | Prevalence |
|---|---|---|---|---|
| #3609 | Position-2 N-terminus residue detector | Detector of the identity of the second residue at the extreme N-terminus of proteins, with strongest preference for small residues (especially Ser, Ala, and Gly; also Thr/Pro), i.e., an N-terminal position-2 signal commonly associated with generic, disordered starts and co-translational N-terminus processing | 10.84 | 2 |
| #6484 | Prion-like low-complexity IDRs | Polar low-complexity intrinsically disordered regions (IDRs)—especially Q/N-rich (prion-like) segments and S/T- and glycine-rich tracts with simple SG/TG/PG repeats—typically located in inter-domain linkers and terminal tails of eukaryotic proteins and often harboring Ser/Thr phosphorylation sites. | 10.56 | 16 |
| #448 | N-terminal leader/targeting segments | N-terminal leader/targeting segments: the feature activates on the extreme N-terminus (first 2–5 residues) of proteins, especially the N-region of signal peptides and organelle transit peptides, and more generally on short, disordered/low-complexity N-terminal tails; strongest at residue ~3 and largely independent of amino-acid identity, occurring across all taxa and functions. | 10.03 | 2 |
| #11504 | Initiator methionine at M1 | Initiator methionine at the very start of the polypeptide chain (M1), i.e., the translation start residue, independent of protein family, taxonomy, membrane association, or presence of signal/leader/propeptide regions; often annotated as post-translationally removed and typically situated in a flexible, coil-like N-terminus. | 8.84 | 2 |
| #4992 | Small-residue disordered N-terminus | Context-dependent free N-terminus signature: short, disordered amino-terminal stretches beginning with the initiator Met followed by residues compatible with MAP cleavage or N-acetylation (e.g., M–G/A/S/T/V, and other contexts including M–D/E/L); strongest emphasis on small residues at positions 2–3; activation is absent when the native N-terminus is structured or starts with a signal peptide/transmembrane segment. | 8.12 | 2 |
| #9998 | Weak N+3 positional cue | Absolute N-terminal positional cue centered near the fourth residue (N+3), independent of amino-acid identity; most often within signal/transit peptides of precursors but also present in non-secreted proteins; the effect is weak and often does not produce a discrete detected site. | 7.84 | 2 |
| #14822 | Folded-domain interface residue detector | A broadly tuned, weak detector of single residues within folded domains, with a mild bias toward sites involved in binding or assembly (protein–protein interfaces, receptor- or calmodulin-binding patches, and small‑molecule/lipid contacts), often falling in alpha‑helices or at loop/strand edges. | 5.56 | 2 |
| #6377 | Interface-adjacent conserved motifs | A "functional-site adjacency" signal that fires at residues within well-ordered secondary structure participating in, or immediately flanking, ligand/cofactor-binding, catalytic, or protein-protein interaction interfaces, with a particularly strong pattern at conserved motif residues of small interaction modules (CCT, SOCS-box, BC-box). | 5.37 | 3 |
| #7985 | Signal peptides and disordered tails | Compositionally biased, hydrophobic/aromatic-rich segments—often in low-structure regions including N-terminal pre-sequences, flexible linkers/tails, and short exposed stretches within mature chains. These regions are enriched for Leu/Val/Ile/Phe/Tyr with Pro/Gly and often include low-complexity repeats (e.g., Asn-rich tracts in Dictyostelium). The concept spans signal/transit peptides of secreted/membrane/organellar proteins and intrinsically disordered tails in soluble enzymes and viral accessory proteins. | 5.30 | 2 |
| #14646 | Short N-terminal leader segment | Short N-terminal segments within the first ~10–40 amino acids, often Lys/Arg-enriched but sometimes purely hydrophobic. These commonly correspond to Sec-type signal peptides, signal anchors, or other short N-terminal segments preceding/overlapping the first hydrophobic helix, and also include disordered N-terminal tails in soluble proteins. | 5.25 | 12 |
| #12470 | Aminergic GPCR TM5-TM6 motif | A feature that fires at conserved sequence motifs in class A aminergic GPCRs, with the strongest hits at a specific cytoplasmic loop motif between TM5 and TM6 (around "SSLER(A/V)AEHAQ") and additional weaker peaks scattered through transmembrane helices 4 and 6 and adjacent cytoplasmic regions. | 4.90 | 2 |
| #7996 | Generic extreme N-terminus detector | Generic extreme N-terminus detector: marks residues around position 5 (occasionally 6–7) at the very start of the polypeptide, most often within the N-region of signal/transit peptides of secreted or organelle-targeted precursors, but also in generally disordered N-termini of cytosolic/nuclear proteins; not motif- or residue-specific | 4.73 | 2 |
| #9395 | Short terminal targeting segment | Terminal or short internal targeting/interaction segment: a short, compositionally biased or hydrophobic patch near a protein terminus, or occasionally an internal low‑complexity loop, that functions as a signal peptide or signal‑anchor (Sec/ER/thylakoid/Tat entry) when hydrophobic, or as a basic/Ser/Lys/Arg/Pro‑rich low‑complexity segment that mediates localization or partner binding in soluble proteins; typically the single prominent terminal segment of short secreted, membrane, or regulatory proteins | 4.61 | 2 |
| #14493 | Short hydrophobic helical runs | Short hydrophobic helical segments rich in I/V/F (sometimes M), recognized in both membrane-targeting/insertion contexts (signal peptides, signal-anchors, transmembrane helices) and in hydrophobic helical patches within otherwise soluble small proteins. The feature flags contiguous aliphatic/hydrophobic runs across diverse proteins, including viral membrane/accessory proteins, secreted peptide/effector precursors, small ORFs/microproteins, and short basic/uncharacterized human proteins. | 4.58 | 2 |
| #5241 | Early N-terminal positional signal | Generic early N-terminus positional signal peaking at residue ~5–7, found broadly within the disordered N-tail of proteins, including both cleavable leader/targeting segments (signal peptides, propeptides) of precursor proteins and disordered N-terminal regions of mature proteins; residue identity is not specific | 4.53 | 2 |
| #7384 | Leucine-biased disordered hydrophobic segments | Leucine-biased recognition of intrinsically disordered, low-complexity hydrophobic segments, including disordered insertions within otherwise structured proteins. | 4.50 | 3 |
| #14891 | Disordered termini and cleavage detector | Residue-level detector of intrinsically disordered, flexible termini and proteolytic processing junctions—especially N-termini (including the first residue of the mature chain after propeptide/leader cleavage)—with no strict amino‑acid specificity and a bias toward small/charged residues; common in small, secreted/precursor and viral proteins but also present in disordered regions of diverse proteins. | 4.04 | 3 |
| #3604 | Acidic Pro/Ser-rich disordered regions | Proline/serine-rich low-complexity and disordered regions, frequently with acidic/PEST-like character; the feature also fires on small proteins and on internal stretches outside obvious low-complexity tracts when local Pro/Arg/Ser content is high. | 3.85 | 6 |
| #5482 | N-terminal targeting presequences | Universal eukaryotic N-terminal targeting presequences: the feature detects short, cleavable leader regions at the extreme N-terminus that direct proteins to organelles or the secretory pathway—especially chloroplast/apicoplast transit peptides and thylakoid lumen signals, but also mitochondrial targeting peptides and classical signal peptides. These segments are Ser/Thr- and small/hydrophobic–rich, enriched in Lys/Arg and depleted of acidic residues, typically low-structure/low-confidence and ending at the maturation cleavage site. | 3.82 | 3 |
| #246 | Regulatory low-complexity IDRs | Intrinsically disordered, low-complexity regulatory segments enriched in acidic/serine/proline/glutamine/glycine residues in eukaryotic proteins—most prominently in transcription factors and in regulatory tails/linkers of signaling/scaffold proteins—corresponding to transactivation/repression or partner-interaction regions adjacent to but outside structured DNA-binding or catalytic domains. | 3.74 | 2 |
| #1135 | Homopolymeric low-complexity tracts | Compositionally biased, low-complexity sequence segments characterized by homopolymeric residue runs; the feature detects local stretches of repeated single amino acids regardless of chemistry (polar, basic, or hydrophobic), most often within disordered or unstructured contexts but also occasionally within folded domains where such runs occur. | 3.48 | 9 |
| #14000 | IDR and signal peptide detector | Generic detector of low-complexity/intrinsically disordered segments and short hydrophobic N‑terminal stretches (signal peptides/first TM anchors), with preference for S/T/P/G/A/N- and N/Q‑rich tracts; largely avoids well‑ordered helical cores | 3.36 | 3 |
| #5337 | Pro/RGG-rich low-complexity IDRs | Intrinsically disordered, low‑complexity basic segments at termini and long loops, enriched in Pro/Gly and/or Arg/Ser (including RG/RGG or S/T clusters), common across eukaryotic and viral proteins. | 3.35 | 10 |
| #11775 | Disordered C-terminal tail hotspots | Short hotspots in intrinsically disordered terminal tails—most often the cytosolic C-termini of membrane proteins (especially GPCRs and single-pass adhesion proteins), but also analogous termini of soluble proteins. | 3.35 | 3 |
| #6036 | Signal peptide hydrophobic h-region | Cleavable N-terminal signal peptides of Sec/SRP-targeted secreted and luminal proteins, with strongest response to the short hydrophobic alpha-helical h-region that drives ER translocation | 3.19 | 5 |
| #8910 | Aliphatic-rich disordered LCRs | Ala/Val/Gly–enriched low‑complexity segments, often within intrinsically disordered or low‑confidence regions of small/unstructured proteins (signal peptides, pro‑peptide extensions, regulatory tails, microproteins), characterized by small aliphatic residues interspersed with sparse acidic residues; composition- rather than function-specific. | 3.19 | 3 |
| #3054 | Basic GP/PTS low-complexity tracts | Intrinsically disordered, low‑complexity segments enriched in glycine/proline and serine/threonine, often containing clusters of basic residues (Lys/Arg) and simple repeats; includes PTS- and GP-rich repeats in secreted/processed peptides and extracellular proteins, as well as basic, Ser/Arg‑rich viral and micropeptide regions. Activation requires extended low‑complexity tracts with these compositions; compact or acidic sequences lacking such tracts are typically not activated. | 3.16 | 3 |
| #12009 | Hydrophobic and leader-like segments | Hydrophobic and/or small/turn-forming sequence segments, including but not limited to classical targeting leaders (signal peptides, signal-anchor TMs, mitochondrial/chloroplast transit peptides). The feature is compositional and responds to short hydrophobic patches, propeptides, low-complexity/Pro/Ser/Thr-rich segments, and amphipathic/disordered stretches that may occur anywhere in the sequence, though early/leader regions are common. | 3.14 | 6 |
| #9946 | Disordered N-termini and coils | Detector for intrinsically disordered, low-structure N‑terminal pre-sequences (signal peptides’ N/C regions, organellar transit peptides, and propeptides) and, more generally, flexible coil/low‑pLDDT segments; strongest bias for the first 10–70 residues but can also mark internal loops in large enzymes and short low‑complexity micropeptides. | 2.97 | 2 |
| #6757 | N-terminal disordered propeptide signature | Generic signature of small proteins, intrinsically disordered and low-complexity segments, and precursor/propeptide regions (S/T/P/G/A-enriched), often at N-termini, rather than structured catalytic or metal-binding motifs | 2.77 | 2 |
Canonical-only features — 12 total (prevalence ≥ 2)
| Feature | Label | Description | Activation | Prevalence |
|---|---|---|---|---|
| #13225 | Membrane hydrophobic helix signature | Hydrophobic alpha-helical membrane-association signature: the feature fires on short clusters of hydrophobic residues that form signal peptides and transmembrane helices (including amphipathic membrane-anchoring helices); in soluble NTPases it often also aligns with a conserved hydrophobic helix in the ATPase core. | 3.19 | 2 |
| #10995 | β-strand–rich extracellular interfaces | β-strand–rich interaction surfaces with strong enrichment in secreted/lumenal protein regions, but not exclusive to them; the feature targets β-strands and adjacent loops that are often post-translationally stabilized (N-glycans) in extracellular proteins, and analogous β-elements in certain intracellular trafficking and phosphoinositide-processing proteins. | 3.14 | 2 |
| #15202 | HEAT/ARM alpha-solenoid scaffold | Alpha-solenoid helical-repeat scaffold (importin-β-like HEAT/ARM repeats) used by karyopherins and other large eukaryotic helical-repeat adaptors; the feature recognizes the continuous arrays of amphipathic α-helices that form flexible HEAT/ARM superhelices underlying nucleocytoplasmic transport and assembly of large complexes. | 2.51 | 2 |
| #2180 | TDG/DG strand-end beta-turn | DG-centered beta-turn motif at the end of β-strands—most often the short Thr–Asp–Gly (TDG) sequence—occurring on exposed β→loop or β→α junctions; prominently realized in von Willebrand factor A (VWA) domains but also present in other folds (e.g., ThDP enzymes) | 2.30 | 2 |
| #2603 | Conserved extramembrane functional hotspots | Conserved non‑transmembrane functional hotspots: the feature highlights family‑signature loci outside membrane spans—either single hallmark residues within soluble enzyme domains or short linear motifs/patches in cytosolic or extracellular/disordered segments of membrane/regulatory proteins—that serve as key determinants of function (e.g., metal/catalytic positioning, structural anchoring, or interaction/gating surfaces). | 2.10 | 2 |
| #554 | Sliding clamp fold detector | Detector of DNA polymerase processivity clamps—PCNA/β-clamp/9-1-1 and related viral processivity factors—keying on the conserved clamp-domain fold, especially repeated loop→β-strand elements within each clamp domain; it cross-activates weakly on short secondary-structure transition segments that mimic these motifs in unrelated proteins | 2.04 | 3 |
| #1265 | Aromatic hydrophobic hotspots | Generic detector of bulky aromatic hydrophobic side chains—especially tryptophan, tyrosine, and phenylalanine—in helical/hydrophobic microenvironments. In membrane proteins it emphasizes the aromatic belt at transmembrane helix boundaries and ligand/solute-binding cores; in soluble enzymes it marks buried aromatic cores or pockets (including nucleotide-binding sites). Overall this reflects an “aromatic/hydrophobic microenvironment” signal rather than a family-specific motif. | 1.98 | 2 |
| #8073 | Exposed charged loop/helix patch | A solvent-exposed, charged loop/short amphipathic helix patch at secondary-structure junctions (loop–helix–loop or strand–helix), often flexible or partially disordered, enriched in acidic/basic residues and frequently containing aromatic residues (e.g., Trp/Tyr). These segments commonly serve as interaction/recognition or modification-prone patches positioned adjacent to—but not comprising—catalytic motifs, and occur broadly in extracellular/periplasmic enzymes, membrane lumenal domains, and cytosolic adaptor/enzymatic proteins. | 1.96 | 2 |
| #14986 | Extended assembly interface regions | Extended, compositionally biased segments that mediate assembly or anchoring—often helical or coiled-coil but sometimes including β-strand-rich oligomerization interfaces—located in terminal or accessory regions (basic or acidic low-complexity runs, or Leu/Ile/Val/Phe-rich stretches), rather than in compact catalytic cores. | 1.81 | 2 |
| #8874 | Cationic processing-site microdomains | Short cationic/low-complexity microdomains (≈15–30 aa) that are enriched at proteolytic processing junctions of secreted precursors and within assembly-prone extracellular fibrils (e.g., curli, hydrophobins), and that also occur as similar disordered/basic patches in periplasmic and intracellular proteins. These regions are often Gly-rich and/or cationic, frequently near di/tri-basic motifs and may include the first conserved Cys of cystine-stabilized peptides; they are typically disordered or minimally structured until engaged. | 1.71 | 2 |
| #15071 | Outer-membrane beta-barrels | Outer-envelope exported proteins of Gram-negative bacteria, with strongest signal on the transmembrane beta-strand walls of outer-membrane beta-barrel proteins (porins, TonB-dependent receptors, Type V autotransporters, and Omp85/organellar homologs), and secondary enrichment for Sec-exported periplasmic/secreted enzymes (e.g., sulfatases, glycosidases, oxidoreductases) that share the outer-envelope/secretory context. | 1.68 | 2 |
| #6830 | Conserved short hydrophobic motif detector | A feature that activates on short conserved hydrophobic/aromatic motifs in two distinct contexts—(i) a C-terminal beta-strand "GQIPE(L/V)IFY" motif in BTB/POZ-domain proteins, and (ii) an internal "AGG(F/Y)(I/T)Y(T/T)" motif in the lumenal catalytic region of beta-1,3-GalNAc transferase 2 (B3GALNT2) orthologs. | 1.63 | 3 |
Shared features by |Δ| activation — 886 total (prevalence ≥ 2)
| Feature | Label | Description | Δ activation | Iso act. | Canon act. | Iso prev. | Canon prev. |
|---|---|---|---|---|---|---|---|
| #9852 | N-terminus activation; hydrophobic helices secondary | Extreme N-terminal regions of proteins, starting at the initiator methionine and extending over a short stretch, with occasional secondary activation at internal hydrophobic/amphipathic helices. | +4.42 | 6.64 | 2.22 | 19 | 4 |
| #220 | Phenylalanine-rich hydrophobic motif detector | Phenylalanine-focused residue identity feature: detects Phe (F) residues, with a preference for F-rich, hydrophobic stretches (e.g., signal peptides and transmembrane helices), but independent of secondary structure or specific function | +4.17 | 10.95 | 6.78 | 10 | 9 |
| #6384 | Widespread activation in folded proteins | Proteins showing broad, diffuse activation across large fractions of their sequence, with peaks frequently occurring in folded regions of single-domain or multi-domain enzymes and structural proteins. | +4.01 | 6.77 | 2.76 | 42 | 12 |
| #10117 | Diffuse low-complexity/disorder signature | A broadly tuned signature of disordered/low-complexity-containing proteins: the feature activates diffusely across long stretches of large multi-domain proteins, with residue-level peaks scattered through both folded and disordered segments. It is common in large, repeat-rich extracellular/surface proteins but also marks regions in diverse intracellular proteins. | +3.25 | 5.35 | 2.10 | 17 | 3 |
| #6176 | Sparse activation in small proteins | Sparse, low-amplitude activation distributed across small or short proteins, with no strict residue preference and peaks landing in a variety of structural contexts. | +2.86 | 6.07 | 3.21 | 5 | 4 |
| #3503 | Cationic/hydrophobic low-complexity segments | Compositionally biased and low-complexity segments enriched in hydrophobic (L/V/I/A), basic (K/R), and Ser/Thr/Pro residues (with underrepresented Trp). The feature marks both cationic Ser/Thr/Pro-enriched segments and hydrophobic leader-like stretches, capturing N-terminal targeting peptides, micropeptides, and internal polybasic/low-complexity motifs in diverse proteins. | +2.65 | 5.58 | 2.93 | 10 | 6 |
| #627 | Generic serine detector | Generic serine detector: the feature marks serine residues, with weaker affinity for threonine (and occasionally proline), and is especially prominent in low-complexity S/T-rich stretches; it is context- and structure-agnostic and does not correspond to a specific functional motif. | +2.29 | 6.82 | 4.53 | 19 | 17 |
| #10782 | Lysine residues and KK/KR motifs | Lysine (K) feature that fires on K residues across diverse proteins, with notable amplification at Lys-rich, low-complexity/disordered segments and clustered basic motifs (KK/KR). | +2.08 | 6.34 | 4.27 | 14 | 13 |
| #8412 | Valine-centered residue detector | Detector that fires on valine residues across diverse sequence contexts, including hydrophobic transmembrane helices and signal peptides as well as Val-containing tandem repeats (elastomeric Gly-rich lamprin-like repeats, Pro/Arg-rich disordered repeats) and isolated Val positions in soluble globular proteins. | +2.00 | 7.20 | 5.21 | 21 | 19 |
| #11526 | Glycine amidation motif detector | Residue-level detector for small/flexible residues—especially glycine—in short, low-structure linkers and proteolytic processing signals of peptide precursors, with a strong preference for the C‑terminal amidation context in which a glycine (amide donor) immediately precedes mono/di‑basic residues (G‑K/R); outside precursors it gives sparse hits on similar small-residue sites in intrinsically disordered regions and occasionally within structured domains across diverse taxa. | +1.93 | 3.81 | 1.88 | 5 | 3 |
| #4900 | Arginine-rich segments and residues | Arginine residue identity/basic-tract feature: primarily marks arginine (R) residues—and dense arginine-rich, low-complexity segments—independent of protein family, fold, or function; shows a strong bias for R over other residues (occasional weak lysine signal), appearing both in disordered/repetitive regions and on individual R within structured domains or near transmembrane boundaries. | +1.80 | 6.39 | 4.58 | 11 | 10 |
| #8050 | Low-confidence intrinsic disorder | Residue-level detector of intrinsically disordered/flexible regions characterized by low predicted structural confidence (low pLDDT), often in low-complexity or unstructured tails, independent of specific secondary-structure assignment | +1.36 | 3.79 | 2.43 | 3 | 2 |
| #13480 | Alanine and small-residue enrichment | A sequence-composition feature that detects small, non-aromatic residues—especially alanine—and their enrichment, lighting up individual Ala residues and stretches enriched in A/G/S/T/P/V (alanine-rich, low-complexity segments) irrespective of protein function or secondary structure. | +1.34 | 6.21 | 4.86 | 10 | 8 |
| #8319 | Amphipathic recognition helices | Short amphipathic alpha-helical “recognition” segments used for binding (DNA, membranes, or protein partners), including the recognition helix of helix-turn-helix DNA-binding domains and N‑terminal targeting/signal helices | +1.22 | 3.10 | 1.88 | 4 | 2 |
| #6803 | Transcription factor activation motifs | Short linear interaction motif–like sites in intrinsically disordered regions of transcription factors, often corresponding to activation/cofactor-binding segments (e.g., the Hox Antp-type hexapeptide/YPWM-containing region), with occasional weaker hits in structured DNA-binding domains | +1.14 | 5.75 | 4.61 | 4 | 3 |
| #6016 | Helix-biased internal methionine detector | Detector for methionine residues, firing on internal Met across diverse proteins with somewhat enhanced response when Met occurs in helical or low-complexity contexts; occasional hits at the initiator Met when embedded in a locally Met- or hydrophobic-rich N-terminus; weak cross-reactivity to other bulky hydrophobics (notably tryptophan). | +1.04 | 6.40 | 5.36 | 3 | 2 |
| #5330 | Low-complexity disordered N-termini | Low-complexity, intrinsically disordered/propeptide-like segments—typically near N-termini—enriched in Gly/Pro/Ser/Ala and basic (Lys/Arg) residues, often in short repeats or polybasic clusters; the feature highlights flexible coils and secondary-structure junctions (helix/strand–coil boundaries) across very small proteins and larger proteins alike. | +0.98 | 3.19 | 2.21 | 5 | 2 |
| #12662 | Sparse short-stretch disordered activations | Sparse, short-stretch activations distributed across diverse protein contexts, with a tendency to fire in non-conserved insert regions, disordered/low-complexity segments, and short N-terminal propeptide regions, but also occurring within structured domains and transmembrane helices. | +0.86 | 2.95 | 2.09 | 6 | 5 |
| #15815 | Basic N-terminal targeting patch | Short, basic/polar N‑terminal leader/transit segment immediately after the initiator methionine (positions ~3–6) — i.e., the positively charged/polar start of signal peptides and organelle transit peptides, and more generally low‑acidic, disordered N‑terminal patches (including occasional cysteine‑rich starts) used for targeting, export, rRNA binding, or membrane topology cues | -0.83 | 6.84 | 7.67 | 8 | 4 |
| #189 | Tryptophan residue detector | A residue-identity detector for tryptophan (W) side chains, with minor cross-activation on other aromatics (Y/F) and small hydrophobics, largely independent of position, domain, structure, or taxonomy; frequently encountered in secreted/viral and disordered contexts but not restricted to them. | +0.71 | 8.55 | 7.84 | 4 | 3 |
| #3392 | Amphipathic interface alpha helices | Generic solvent‑exposed, charged/amphipathic alpha‑helical segments that serve as macromolecular interface scaffolds (protein–protein and nucleic‑acid–binding helices), rather than catalytic residues; a broadly used structural motif across taxa | +0.66 | 6.48 | 5.82 | 7 | 7 |
| #16243 | Structured-region leucine detector | Generic detector of leucine side chains in structured regions of folded domains, with occasional weaker responses to other hydrophobics; largely indifferent to specific functional motifs or protein class. | +0.60 | 6.64 | 6.05 | 23 | 20 |
| #15471 | Internal domain motif hotspots | Short internal sequence motifs within large catalytic or structural protein domains, with peaks typically falling on a single dominant residue flanked by a mix of small (Gly/Ala/Pro), aromatic (Tyr/Phe), and polar residues; activation is sparse across each protein and concentrated at a narrow internal hotspot. | -0.58 | 3.97 | 4.55 | 2 | 2 |
| #9000 | Glutamate-biased acidic tract detector | Detector of glutamate identity and glutamate-enriched acidic tracts: strong activation on E residues, especially within acidic, low‑complexity/disordered regions; weaker, sporadic responses on D; largely domain-, function-, and taxonomy-agnostic. | +0.55 | 5.94 | 5.39 | 18 | 17 |
| #6544 | TESPA1/ITPRID cassette hotspot | Mammal-specific, family-restricted short internal segment around residues 200–250 shared by TESPA1 and ITPRID proteins; the model selects a single residue-level hotspot within this segment independent of residue identity. | +0.49 | 7.61 | 7.12 | 16 | 16 |
| #14534 | Unknown generic feature | Unknown generic feature | +12.81 | 31.53 | 18.72 | 215 | 196 |
| #9005 | Unknown generic feature | Unknown generic feature | +12.12 | 24.09 | 11.98 | 167 | 156 |
| #1803 | Unknown generic feature | Unknown generic feature | +7.84 | 23.98 | 16.14 | 210 | 196 |
| #14895 | Unknown generic feature | Unknown generic feature | -1.00 | 20.08 | 21.08 | 219 | 204 |
| #9214 | Unknown generic feature | Unknown generic feature | -0.98 | 15.98 | 16.95 | 216 | 200 |
Part 2 · Differential coordinates
Features firing on just the isoform-unique (extension / alt-frame) residues.
Unique-region features — 138 distinct (prevalence ≥ 2)
| Feature | Label | Description | Activation | Prevalence |
|---|---|---|---|---|
| #6484 | Prion-like low-complexity IDRs | Polar low-complexity intrinsically disordered regions (IDRs)—especially Q/N-rich (prion-like) segments and S/T- and glycine-rich tracts with simple SG/TG/PG repeats—typically located in inter-domain linkers and terminal tails of eukaryotic proteins and often harboring Ser/Thr phosphorylation sites. | 10.56 | 15 |
| #1136 | Broad HORMA-domain activation N-terminal peak | HORMA-domain meiotic/checkpoint proteins, with activation distributed across the folded HORMA domain itself. | 8.67 | 14 |
| #8412 | Valine-centered residue detector | Detector that fires on valine residues across diverse sequence contexts, including hydrophobic transmembrane helices and signal peptides as well as Val-containing tandem repeats (elastomeric Gly-rich lamprin-like repeats, Pro/Arg-rich disordered repeats) and isolated Val positions in soluble globular proteins. | 7.20 | 2 |
| #627 | Generic serine detector | Generic serine detector: the feature marks serine residues, with weaker affinity for threonine (and occasionally proline), and is especially prominent in low-complexity S/T-rich stretches; it is context- and structure-agnostic and does not correspond to a specific functional motif. | 6.82 | 2 |
| #6384 | Widespread activation in folded proteins | Proteins showing broad, diffuse activation across large fractions of their sequence, with peaks frequently occurring in folded regions of single-domain or multi-domain enzymes and structural proteins. | 6.77 | 15 |
| #16243 | Structured-region leucine detector | Generic detector of leucine side chains in structured regions of folded domains, with occasional weaker responses to other hydrophobics; largely indifferent to specific functional motifs or protein class. | 6.64 | 3 |
| #9852 | N-terminus activation; hydrophobic helices secondary | Extreme N-terminal regions of proteins, starting at the initiator methionine and extending over a short stretch, with occasional secondary activation at internal hydrophobic/amphipathic helices. | 6.64 | 15 |
| #13480 | Alanine and small-residue enrichment | A sequence-composition feature that detects small, non-aromatic residues—especially alanine—and their enrichment, lighting up individual Ala residues and stretches enriched in A/G/S/T/P/V (alanine-rich, low-complexity segments) irrespective of protein function or secondary structure. | 6.21 | 2 |
| #15815 | Basic N-terminal targeting patch | Short, basic/polar N‑terminal leader/transit segment immediately after the initiator methionine (positions ~3–6) — i.e., the positively charged/polar start of signal peptides and organelle transit peptides, and more generally low‑acidic, disordered N‑terminal patches (including occasional cysteine‑rich starts) used for targeting, export, rRNA binding, or membrane topology cues | 6.09 | 4 |
| #13334 | N-terminal IDR boundary | Recognition of short, low-complexity, intrinsically disordered N-terminal tails immediately upstream of the first folded domain; these segments are often Ser/Thr/Pro/Gly/Ala-biased and sometimes extend a few residues into the initial helix or the very beginning of the first domain (domain boundary/disorder-to-order transition), especially in transcription regulators and co-regulators. | 5.79 | 15 |
| #2302 | Seipin post-TM lumenal/propeptide detector | Detector of post-transmembrane lumenal segments in ER membrane proteins of the seipin family, with additional activation on the propeptide regions of TGF-β superfamily precursors (e.g., GDF-10/BMP-3B). | 5.62 | 14 |
| #11633 | Assembly scaffold interaction modules | Protein–protein interaction modules in eukaryotic and bacterial assembly/scaffold proteins, prominently HORMA-domain folds and analogous α/β interaction cores, often adjoining low-complexity Ser/Thr/Pro- and Q/N-rich segments, mediating incorporation into large complexes (kinetochore, autophagy scaffolds, ER–mitochondria tethers, RNA-binding assemblies, dynein complexes, Hsp90 co-chaperone systems, COMMD-containing complexes). | 5.58 | 14 |
| #3503 | Cationic/hydrophobic low-complexity segments | Compositionally biased and low-complexity segments enriched in hydrophobic (L/V/I/A), basic (K/R), and Ser/Thr/Pro residues (with underrepresented Trp). The feature marks both cationic Ser/Thr/Pro-enriched segments and hydrophobic leader-like stretches, capturing N-terminal targeting peptides, micropeptides, and internal polybasic/low-complexity motifs in diverse proteins. | 5.58 | 3 |
| #10117 | Diffuse low-complexity/disorder signature | A broadly tuned signature of disordered/low-complexity-containing proteins: the feature activates diffusely across long stretches of large multi-domain proteins, with residue-level peaks scattered through both folded and disordered segments. It is common in large, repeat-rich extracellular/surface proteins but also marks regions in diverse intracellular proteins. | 5.35 | 14 |
| #14646 | Short N-terminal leader segment | Short N-terminal segments within the first ~10–40 amino acids, often Lys/Arg-enriched but sometimes purely hydrophobic. These commonly correspond to Sec-type signal peptides, signal anchors, or other short N-terminal segments preceding/overlapping the first hydrophobic helix, and also include disordered N-terminal tails in soluble proteins. | 5.25 | 12 |
| #7572 | Conserved catalytic helix motif | A conserved internal sequence/structural motif within enzyme catalytic domains, prominently exemplified by the "DRL(V/I)G(x)YEE" segment of the glutamate mutase epsilon subunit, where activation peaks on a short hydrophobic-aromatic stretch embedded in an α-helix close to cofactor/substrate binding residues. | 5.25 | 7 |
| #1594 | Disordered tails, linkers, propeptides | Intrinsically disordered, low‑complexity linear regions (IDRs)—typically polar/charged and Ser/Thr/Pro/Gly‑rich—found most often at N‑terminal tails, cytosolic linkers, and propeptides; the feature avoids well‑folded domains but can extend into marginally structured, low‑complexity coiled‑coils or short amphipathic helices used as flexible tethers or assembly elements. | 4.95 | 13 |
| #9395 | Short terminal targeting segment | Terminal or short internal targeting/interaction segment: a short, compositionally biased or hydrophobic patch near a protein terminus, or occasionally an internal low‑complexity loop, that functions as a signal peptide or signal‑anchor (Sec/ER/thylakoid/Tat entry) when hydrophobic, or as a basic/Ser/Lys/Arg/Pro‑rich low‑complexity segment that mediates localization or partner binding in soluble proteins; typically the single prominent terminal segment of short secreted, membrane, or regulatory proteins | 4.61 | 2 |
| #14493 | Short hydrophobic helical runs | Short hydrophobic helical segments rich in I/V/F (sometimes M), recognized in both membrane-targeting/insertion contexts (signal peptides, signal-anchors, transmembrane helices) and in hydrophobic helical patches within otherwise soluble small proteins. The feature flags contiguous aliphatic/hydrophobic runs across diverse proteins, including viral membrane/accessory proteins, secreted peptide/effector precursors, small ORFs/microproteins, and short basic/uncharacterized human proteins. | 4.58 | 2 |
| #7384 | Leucine-biased disordered hydrophobic segments | Leucine-biased recognition of intrinsically disordered, low-complexity hydrophobic segments, including disordered insertions within otherwise structured proteins. | 4.50 | 3 |
| #15338 | HECT E3 catalytic domain | The HECT catalytic domain of HECT-type E3 ubiquitin ligases, covering the C-terminal catalytic fold (including the catalytic cysteine forming the glycyl thioester intermediate) and extending broadly across the domain. | 4.46 | 13 |
| #10704 | N-terminal PEST-like IDRs | Low-complexity, often acidic/proline-rich intrinsically disordered N-terminal tails of intracellular eukaryotic proteins, frequently overlapping annotated PEST-like segments. | 4.24 | 15 |
| #12109 | Proline-rich low-complexity IDRs | Eukaryotic intrinsically disordered, low‑complexity linkers and tails enriched in Pro/Ser/Thr/Gln/Gly—often containing proline‑rich motifs and S/T‑P dipeptides—that act as multivalent, PTM‑dense interaction platforms in large scaffold and regulatory proteins. | 4.20 | 12 |
| #14891 | Disordered termini and cleavage detector | Residue-level detector of intrinsically disordered, flexible termini and proteolytic processing junctions—especially N-termini (including the first residue of the mature chain after propeptide/leader cleavage)—with no strict amino‑acid specificity and a bias toward small/charged residues; common in small, secreted/precursor and viral proteins but also present in disordered regions of diverse proteins. | 4.04 | 2 |
| #14534 | Unknown generic feature | Unknown generic feature | 31.53 | 15 |
| #9005 | Unknown generic feature | Unknown generic feature | 24.09 | 15 |
| #1803 | Unknown generic feature | Unknown generic feature | 23.98 | 15 |
| #14895 | Unknown generic feature | Unknown generic feature | 20.08 | 15 |
| #9214 | Unknown generic feature | Unknown generic feature | 15.98 | 15 |
| #9194 | Unknown generic feature | Unknown generic feature | 14.45 | 15 |
Top-K sparse-autoencoder activations on the ESM-C residual stream. Activation is a feature's peak value over its region; Prevalence is the number of residues it fires on; Δ activation is isoform − canonical. Only the top 30 features per category are saved; generic / "unknown" features are hidden until you expand a table. Read more about SAE features →
Clinical variants
Differential region — N-terminal extension (isoform-unique)
| Pos (iso) | AA change | Consequence | Source | Clin. sig. | AF (gnomAD) | Impact | AlphaMissense | ESM-C ΔLLR | Link |
|---|---|---|---|---|---|---|---|---|---|
| 0 | — | frameshift_variant | gnomAD | — | 2.19e-04 | LoF | — | — | chr4-120066778-A-AGC |
| 0 | L→P | missense_variant | gnomAD | — | 5.47e-06 | — | N/A | — | chr4-120066778-A-G |
| 0 | L→L | synonymous_variant | COSMIC | — | — | — | N/A | — | COSV56636693 |
| 1 | S→S | synonymous_variant | gnomAD | — | 3.74e-06 | — | N/A | 0.00 | chr4-120066774-G-A |
| 1 | S→S | synonymous_variant | gnomAD | — | 2.24e-06 | — | N/A | 0.00 | chr4-120066774-G-C |
| 1 | S→S | synonymous_variant | gnomAD | — | 8.97e-06 | — | N/A | 0.00 | chr4-120066774-G-T |
| 2 | A→A | synonymous_variant | gnomAD | — | 4.41e-06 | — | N/A | 0.00 | chr4-120066771-C-T |
| 2 | A→T | missense_variant | gnomAD | — | 1.50e-06 | — | N/A | -0.62 | chr4-120066773-C-T |
| 3 | E→E | synonymous_variant | gnomAD | — | 7.24e-07 | — | N/A | 0.00 | chr4-120066768-C-T |
| 3 | E→G | missense_variant | gnomAD | — | 7.29e-07 | — | N/A | 0.70 | chr4-120066769-T-C |
| 3 | E→Q | missense_variant | gnomAD | — | 7.35e-07 | — | N/A | -0.58 | chr4-120066770-C-G |
| 4 | W→R | missense_variant | gnomAD | — | 7.25e-07 | — | N/A | 1.90 | chr4-120066767-A-T |
| 5 | K→N | missense_variant | gnomAD | — | 7.10e-07 | — | N/A | -0.73 | chr4-120066762-C-A |
| 5 | K→N | missense_variant | gnomAD | — | 7.10e-07 | — | N/A | -0.73 | chr4-120066762-C-G |
| 5 | K→R | missense_variant | gnomAD | — | 4.97e-06 | — | N/A | 0.95 | chr4-120066763-T-C |
| 5 | K→E | missense_variant | gnomAD | — | 2.14e-06 | — | N/A | -0.17 | chr4-120066764-T-C |
| 6 | R→R | synonymous_variant | gnomAD | — | 1.27e-05 | — | N/A | 0.00 | chr4-120066759-G-A |
| 6 | R→C | missense_variant | gnomAD | — | 1.42e-06 | — | N/A | -0.61 | chr4-120066761-G-A |
| 6 | R→G | missense_variant | gnomAD | — | 2.84e-06 | — | N/A | -0.36 | chr4-120066761-G-C |
| 6 | R→C | missense_variant | COSMIC | — | — | — | N/A | -0.61 | COSV56636912 |
| 7 | V→V | synonymous_variant | gnomAD | — | 8.48e-06 | — | N/A | 0.00 | chr4-120066756-C-T |
| 7 | V→L | missense_variant | gnomAD | — | 2.82e-06 | — | N/A | 0.53 | chr4-120066758-C-A |
| 8 | L→F | missense_variant | gnomAD | — | 9.81e-06 | — | N/A | -0.34 | chr4-120066755-G-A |
| 8 | L→V | missense_variant | gnomAD | — | 1.68e-05 | — | N/A | -0.59 | chr4-120066755-G-C |
| 9 | — | frameshift_variant | gnomAD | — | 6.99e-07 | LoF | — | — | chr4-120066750-CA-C |
| 9 | L→S | missense_variant | gnomAD | — | 6.99e-07 | — | N/A | -0.27 | chr4-120066751-A-G |
| 10 | F→S | missense_variant | gnomAD | — | 1.39e-06 | — | N/A | 1.00 | chr4-120066748-A-G |
| 11 | — | frameshift_variant | gnomAD | — | 6.95e-07 | LoF | — | — | chr4-120066744-CACAA-C |
| 11 | V→E | missense_variant | gnomAD | — | 6.95e-07 | — | N/A | -1.11 | chr4-120066745-A-T |
| 11 | V→L | missense_variant | gnomAD | — | 2.09e-06 | — | N/A | 0.80 | chr4-120066746-C-A |
| 11 | V→L | missense_variant | gnomAD | — | 6.97e-07 | — | N/A | 0.80 | chr4-120066746-C-G |
| 12 | S→F | missense_variant | gnomAD | — | 1.39e-06 | — | N/A | -0.67 | chr4-120066742-G-A |
| 12 | S→Y | missense_variant | gnomAD | — | 2.78e-06 | — | N/A | -1.86 | chr4-120066742-G-T |
| 13 | L→L | synonymous_variant | gnomAD | — | 6.93e-07 | — | N/A | 0.00 | chr4-120066738-C-T |
| 13 | L→R | missense_variant | gnomAD | — | 3.47e-06 | — | N/A | -0.42 | chr4-120066739-A-C |
| 13 | L→Q | missense_variant | gnomAD | — | 1.39e-06 | — | N/A | -1.55 | chr4-120066739-A-T |
| 13 | L→L | synonymous_variant | gnomAD | — | 1.39e-06 | — | N/A | 0.00 | chr4-120066740-G-A |
| 14 | A→A | synonymous_variant | gnomAD | — | 2.77e-06 | — | N/A | 0.00 | chr4-120066735-G-A |
| 14 | A→V | missense_variant | gnomAD | — | 6.93e-07 | — | N/A | -0.44 | chr4-120066736-G-A |
| 14 | A→D | missense_variant | gnomAD | — | 6.93e-07 | — | N/A | -1.47 | chr4-120066736-G-T |
| 14 | A→S | missense_variant | COSMIC | — | — | — | N/A | -0.59 | COSV99633801 |
41 variants in the differential region.
Shared canonical core — sequence common to canonical and isoform; AlphaMissense applies here
| Pos (iso) | AA change | Consequence | Source | Clin. sig. | AF (gnomAD) | Impact | AlphaMissense | ESM-C ΔLLR | Link |
|---|---|---|---|---|---|---|---|---|---|
| 15 | M→T | missense_variant | gnomAD | — | 1.38e-06 | damaging | — | -9.37 | chr4-120066733-A-G |
| 15 | M→K | missense_variant | gnomAD | — | 6.92e-07 | damaging | — | -10.81 | chr4-120066733-A-T |
| 15 | M→V | missense_variant | gnomAD | — | 6.92e-07 | damaging | — | -8.87 | chr4-120066734-T-C |
| 15 | — | frameshift_variant | COSMIC | — | — | LoF | — | — | COSV99634044 |
| 16 | A→A | synonymous_variant | gnomAD | — | 1.38e-06 | — | — | 0.00 | chr4-120066729-C-T |
| 16 | A→V | missense_variant | gnomAD | — | 1.11e-05 | damaging | likely_pathogenic (0.60) | -7.98 | chr4-120066730-G-A |
| 16 | A→E | missense_variant | gnomAD | — | 6.92e-07 | damaging | ambiguous (0.34) | -8.11 | chr4-120066730-G-T |
| 16 | A→S | missense_variant | gnomAD | — | 6.91e-07 | — | likely_benign (0.13) | -5.20 | chr4-120066731-C-A |
| 16 | A→T | missense_variant | gnomAD | — | 1.73e-05 | — | likely_benign (0.33) | -5.05 | chr4-120066731-C-T |
| 17 | L→L | synonymous_variant | gnomAD | — | 6.90e-07 | — | — | 0.00 | chr4-120066726-C-T |
| 17 | L→R | missense_variant | COSMIC | — | — | — | likely_benign (0.05) | -7.25 | COSV99633902 |
| 18 | Q→* | stop_gained | gnomAD | — | 1.38e-06 | LoF | — | — | chr4-120066725-G-A |
| 19 | L→L | synonymous_variant | gnomAD | — | 1.38e-06 | — | — | 0.00 | chr4-120066720-G-A |
| 19 | L→L | synonymous_variant | gnomAD | — | 1.38e-06 | — | — | 0.00 | chr4-120066720-G-C |
| 19 | L→H | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_benign (0.14) | -8.68 | chr4-120066721-A-T |
| 19 | L→F | missense_variant | gnomAD | — | 3.45e-06 | — | likely_benign (0.11) | -6.81 | chr4-120066722-G-A |
| 19 | L→V | missense_variant | gnomAD | — | 1.38e-06 | — | likely_benign (0.06) | -6.46 | chr4-120066722-G-C |
| 19 | L→I | missense_variant | gnomAD | — | 2.07e-06 | — | likely_benign (0.07) | -6.90 | chr4-120066722-G-T |
| 19 | L→L | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637843 |
| 20 | S→F | missense_variant | gnomAD | — | 6.90e-07 | damaging | ambiguous (0.34) | -8.62 | chr4-120066718-G-A |
| 21 | R→R | synonymous_variant | gnomAD | — | 4.83e-06 | — | — | 0.00 | chr4-120066714-C-T |
| 21 | R→Q | missense_variant | gnomAD | — | 2.21e-05 | — | likely_benign (0.17) | -6.23 | chr4-120066715-C-T |
| 21 | R→W | missense_variant | gnomAD | — | 6.90e-07 | damaging | ambiguous (0.52) | -8.23 | chr4-120066716-G-A |
| 21 | R→G | missense_variant | gnomAD | — | 1.24e-05 | — | likely_benign (0.12) | -6.55 | chr4-120066716-G-C |
| 21 | R→Q | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.17) | -6.23 | ClinVar:3541916 |
| 22 | E→E | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066711-C-T |
| 22 | E→V | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_benign (0.32) | -9.29 | chr4-120066712-T-A |
| 22 | — | frameshift_variant | gnomAD | — | 6.90e-07 | LoF | — | — | chr4-120066712-TC-T |
| 22 | E→K | missense_variant | gnomAD | — | 4.83e-06 | damaging | ambiguous (0.44) | -8.23 | chr4-120066713-C-T |
| 23 | Q→Q | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066708-C-T |
| 23 | Q→Q | synonymous_variant | ClinVar | Likely benign | — | — | — | 0.00 | ClinVar:2655059 |
| 23 | Q→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636507 |
| 24 | G→G | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066705-T-C |
| 24 | G→R | missense_variant | gnomAD | — | 2.76e-06 | damaging | likely_pathogenic (0.89) | -8.56 | chr4-120066707-C-T |
| 24 | G→R | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_pathogenic (0.89) | -8.56 | ClinVar:2481387 |
| 24 | G→G | synonymous_variant | ClinVar | Likely benign | — | — | — | 0.00 | ClinVar:2655058 |
| 25 | I→M | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.80) | -10.37 | chr4-120066702-G-C |
| 25 | I→T | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_pathogenic (0.98) | -10.87 | chr4-120066703-A-G |
| 25 | I→V | missense_variant | gnomAD | — | 6.89e-06 | — | likely_benign (0.28) | -7.12 | chr4-120066704-T-C |
| 25 | I→V | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.28) | -7.12 | ClinVar:2490789 |
| 25 | I→I | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV106426012 |
| 25 | I→N | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.98) | -12.25 | COSV56636743 |
| 26 | T→T | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066699-G-A |
| 27 | L→P | missense_variant | gnomAD | — | 8.95e-06 | damaging | likely_pathogenic (0.99) | -11.44 | chr4-120066697-A-G |
| 27 | L→M | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.81) | -12.94 | chr4-120066698-G-T |
| 27 | L→L | synonymous_variant | ClinVar | Likely benign | — | — | — | 0.00 | ClinVar:2655057 |
| 27 | L→M | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.81) | -12.94 | COSV99633896 |
| 28 | R→R | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066693-G-T |
| 29 | G→G | synonymous_variant | gnomAD | — | 2.75e-06 | — | — | 0.00 | chr4-120066690-C-G |
| 29 | G→G | synonymous_variant | gnomAD | — | 1.24e-05 | — | — | 0.00 | chr4-120066690-C-T |
| 29 | G→R | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (1.00) | -10.12 | chr4-120066692-C-G |
| 29 | G→R | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (1.00) | -10.12 | COSV56637063 |
| 31 | A→A | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066684-G-C |
| 31 | A→A | synonymous_variant | gnomAD | — | 1.38e-06 | — | — | 0.00 | chr4-120066684-G-T |
| 31 | A→V | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.92) | -8.25 | chr4-120066685-G-A |
| 31 | A→S | missense_variant | gnomAD | — | 6.89e-07 | — | likely_benign (0.29) | -7.50 | chr4-120066686-C-A |
| 31 | A→T | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.78) | -7.62 | chr4-120066686-C-T |
| 32 | E→K | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_pathogenic (0.68) | -9.80 | chr4-120066683-C-T |
| 32 | E→E | synonymous_variant | ClinVar | Likely benign | — | — | — | 0.00 | ClinVar:2655056 |
| 33 | I→M | missense_variant | gnomAD | — | 1.38e-06 | — | likely_benign (0.16) | -7.18 | chr4-120066678-G-C |
| 33 | I→I | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066678-G-T |
| 34 | V→A | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.96) | -10.94 | chr4-120066676-A-G |
| 34 | V→L | missense_variant | gnomAD | — | 2.07e-06 | damaging | likely_pathogenic (0.97) | -11.31 | chr4-120066677-C-G |
| 35 | A→A | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066672-G-A |
| 35 | A→T | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.67) | -7.68 | chr4-120066674-C-T |
| 35 | A→V | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.90) | -8.81 | COSV56637607 |
| 36 | E→E | synonymous_variant | gnomAD | — | 8.27e-06 | — | — | 0.00 | chr4-120066669-C-T |
| 36 | E→D | missense_variant | COSMIC | — | — | — | ambiguous (0.48) | -7.37 | COSV99633714 |
| 37 | F→L | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (1.00) | -10.12 | chr4-120066668-A-G |
| 37 | F→F | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56636758 |
| 37 | F→L | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (1.00) | -10.12 | COSV56636790 |
| 38 | F→F | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120066663-G-A |
| 38 | F→S | missense_variant | gnomAD | — | 2.07e-06 | damaging | likely_pathogenic (0.99) | -14.12 | chr4-120066664-A-G |
| 39 | S→S | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120065817-T-A |
| 39 | S→A | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_benign (0.10) | -7.52 | chr4-120066662-A-C |
| 39 | — | frameshift_variant | gnomAD | — | 2.07e-06 | LoF | — | — | chr4-120066662-AG-A |
| 39 | S→L | missense_variant | COSMIC | — | — | damaging | likely_benign (0.27) | -8.56 | COSV56637555 |
| 40 | F→F | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120065814-G-A |
| 40 | F→L | missense_variant | gnomAD | — | 8.90e-06 | damaging | likely_pathogenic (0.99) | -8.68 | chr4-120065814-G-C |
| 41 | G→G | synonymous_variant | gnomAD | — | 3.63e-05 | — | — | 0.00 | chr4-120065811-G-A |
| 41 | G→D | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (1.00) | -12.62 | chr4-120065812-C-T |
| 41 | G→S | missense_variant | gnomAD | — | 2.05e-06 | damaging | likely_pathogenic (0.79) | -7.87 | chr4-120065813-C-T |
| 41 | G→G | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56636895 |
| 42 | I→I | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120065808-G-A |
| 42 | I→F | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.85) | -11.62 | chr4-120065810-T-A |
| 46 | L→L | synonymous_variant | gnomAD | — | 1.57e-05 | — | — | 0.00 | chr4-120065796-T-C |
| 47 | Y→* | stop_gained | gnomAD | — | 6.84e-07 | LoF | — | — | chr4-120065793-A-T |
| 47 | Y→H | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.96) | -8.81 | chr4-120065795-A-G |
| 49 | R→H | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.99) | -11.31 | chr4-120065788-C-T |
| 49 | R→C | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.99) | -11.44 | COSV56636453 |
| 50 | G→G | synonymous_variant | gnomAD | — | 2.05e-06 | — | — | 0.00 | chr4-120065784-G-C |
| 51 | I→M | missense_variant | gnomAD | — | 2.05e-06 | damaging | likely_pathogenic (0.67) | -8.43 | chr4-120065781-T-C |
| 51 | I→V | missense_variant | gnomAD | — | 6.84e-07 | — | likely_benign (0.13) | -6.25 | chr4-120065783-T-C |
| 51 | I→L | missense_variant | gnomAD | — | 6.84e-07 | — | likely_benign (0.23) | -7.18 | chr4-120065783-T-G |
| 51 | I→M | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.67) | -8.43 | COSV56637152 |
| 52 | Y→S | missense_variant | gnomAD | — | 2.05e-06 | damaging | likely_pathogenic (0.96) | -12.62 | chr4-120065779-T-G |
| 52 | Y→C | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_pathogenic (0.91) | -12.06 | ClinVar:2337132 |
| 53 | P→P | synonymous_variant | gnomAD | — | 6.84e-07 | — | — | 0.00 | chr4-120065775-T-C |
| 54 | S→S | synonymous_variant | gnomAD | — | 6.84e-06 | — | — | 0.00 | chr4-120065772-A-T |
| 54 | S→C | missense_variant | gnomAD | — | 2.05e-06 | damaging | likely_benign (0.15) | -9.02 | chr4-120065773-G-C |
| 56 | T→T | synonymous_variant | gnomAD | — | 2.05e-06 | — | — | 0.00 | chr4-120065766-G-A |
| 56 | T→N | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_benign (0.16) | -8.18 | chr4-120065767-G-T |
| 58 | T→I | missense_variant | gnomAD | — | 3.42e-06 | — | likely_benign (0.26) | -6.92 | chr4-120065761-G-A |
| 58 | T→I | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.26) | -6.92 | ClinVar:2314971 |
| 59 | R→G | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.82) | -9.50 | chr4-120065759-G-C |
| 59 | R→R | synonymous_variant | gnomAD | — | 6.84e-07 | — | — | 0.00 | chr4-120065759-G-T |
| 59 | R→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636783 |
| 60 | V→V | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120065754-C-T |
| 60 | V→A | missense_variant | gnomAD | — | 6.84e-07 | — | ambiguous (0.39) | -5.87 | chr4-120065755-A-G |
| 61 | Q→P | missense_variant | gnomAD | — | 2.05e-06 | damaging | likely_benign (0.27) | -8.50 | chr4-120065752-T-G |
| 61 | Q→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV99634048 |
| 61 | Q→Q | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56636984 |
| 61 | Q→R | missense_variant | COSMIC | — | — | damaging | likely_benign (0.32) | -9.25 | COSV105896543 |
| 62 | K→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636610 |
| 63 | Y→Y | synonymous_variant | gnomAD | — | 4.31e-05 | — | — | 0.00 | chr4-120065745-G-A |
| 63 | Y→C | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.98) | -9.81 | COSV56636603 |
| 64 | G→R | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.97) | -10.25 | COSV106426007 |
| 64 | G→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636827 |
| 65 | L→F | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.91) | -9.62 | chr4-120065741-G-A |
| 66 | T→T | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120065736-G-A |
| 66 | T→T | synonymous_variant | gnomAD | — | 6.84e-07 | — | — | 0.00 | chr4-120065736-G-C |
| 66 | T→I | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.77) | -8.68 | chr4-120065737-G-A |
| 67 | L→F | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.77) | -9.87 | chr4-120065733-C-G |
| 67 | — | frameshift_variant | gnomAD | — | 8.21e-06 | LoF | — | — | chr4-120065733-CA-C |
| 67 | L→W | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.98) | -13.31 | chr4-120065734-A-C |
| 68 | L→F | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_benign (0.26) | -8.69 | chr4-120065732-G-A |
| 69 | V→L | missense_variant | COSMIC | — | — | — | likely_benign (0.32) | -7.34 | COSV56636970 |
| 71 | T→A | missense_variant | gnomAD | — | 2.12e-05 | — | likely_benign (0.10) | -5.80 | chr4-120065723-T-C |
| 74 | E→Q | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_benign (0.13) | -7.58 | chr4-120065714-C-G |
| 76 | — | frameshift_variant | gnomAD | — | 6.84e-07 | LoF | — | — | chr4-120065708-TG-T |
| 77 | K→R | missense_variant | gnomAD | — | 6.84e-07 | — | likely_benign (0.08) | -5.92 | chr4-120065704-T-C |
| 77 | K→* | stop_gained | gnomAD | — | 6.84e-07 | LoF | — | — | chr4-120065705-T-A |
| 78 | Y→F | missense_variant | gnomAD | — | 2.74e-06 | — | ambiguous (0.38) | -6.94 | chr4-120065701-T-A |
| 78 | Y→C | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.96) | -10.00 | chr4-120065701-T-C |
| 78 | Y→N | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.98) | -10.81 | COSV99633708 |
| 79 | L→L | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120065697-T-C |
| 79 | L→L | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120065697-T-G |
| 79 | — | frameshift_variant | gnomAD | — | 6.84e-07 | LoF | — | — | chr4-120065697-TA-T |
| 79 | L→I | missense_variant | gnomAD | — | 1.21e-04 | damaging | likely_benign (0.17) | -8.31 | chr4-120065699-G-T |
| 80 | N→S | missense_variant | gnomAD | — | 2.74e-06 | — | likely_benign (0.07) | -3.68 | chr4-120065695-T-C |
| 80 | N→N | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV108109490 |
| 81 | N→N | synonymous_variant | gnomAD | — | 2.05e-06 | — | — | 0.00 | chr4-120065691-A-G |
| 81 | N→Y | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_benign (0.16) | -8.23 | chr4-120065693-T-A |
| 81 | N→Y | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_benign (0.16) | -8.23 | ClinVar:3869470 |
| 82 | V→G | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (0.89) | -11.56 | chr4-120065689-A-C |
| 82 | V→L | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.88) | -8.69 | chr4-120065690-C-A |
| 84 | E→K | missense_variant | COSMIC | — | — | damaging | likely_benign (0.14) | -7.81 | COSV56636425 |
| 85 | Q→Q | synonymous_variant | gnomAD | — | 1.57e-05 | — | — | 0.00 | chr4-120065679-T-C |
| 86 | L→L | synonymous_variant | gnomAD | — | 4.11e-06 | — | — | 0.00 | chr4-120065676-C-T |
| 87 | K→R | missense_variant | gnomAD | — | 6.84e-07 | — | likely_benign (0.10) | -4.08 | chr4-120065674-T-C |
| 88 | D→G | missense_variant | gnomAD | — | 6.88e-07 | — | likely_benign (0.12) | -5.71 | chr4-120062095-T-C |
| 88 | D→H | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_benign (0.28) | -9.40 | chr4-120065672-C-G |
| 89 | W→L | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.93) | -10.50 | COSV99633853 |
| 90 | L→L | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120062088-T-C |
| 90 | — | frameshift_variant | gnomAD | — | 6.18e-06 | LoF | — | — | chr4-120062090-A-AC |
| 91 | Y→C | missense_variant | gnomAD | — | 2.74e-06 | — | likely_benign (0.07) | -5.45 | chr4-120062086-T-C |
| 91 | Y→F | missense_variant | COSMIC | — | — | — | likely_benign (0.08) | -4.57 | COSV56636540 |
| 91 | Y→H | missense_variant | COSMIC | — | — | — | likely_benign (0.13) | -6.64 | COSV56637585 |
| 92 | K→N | missense_variant | gnomAD | — | 1.51e-05 | — | likely_benign (0.19) | -6.30 | chr4-120062082-C-G |
| 92 | K→K | synonymous_variant | gnomAD | — | 3.43e-06 | — | — | 0.00 | chr4-120062082-C-T |
| 92 | K→R | missense_variant | gnomAD | — | 1.23e-05 | — | likely_benign (0.07) | -5.96 | chr4-120062083-T-C |
| 92 | K→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56637871 |
| 93 | C→Y | missense_variant | gnomAD | — | 1.37e-06 | damaging | ambiguous (0.51) | -8.62 | chr4-120062080-C-T |
| 93 | C→S | missense_variant | gnomAD | — | 2.06e-06 | — | ambiguous (0.41) | -7.19 | chr4-120062081-A-T |
| 94 | S→S | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120062076-T-A |
| 94 | S→S | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120062076-T-C |
| 94 | S→L | missense_variant | gnomAD | — | 6.85e-07 | — | likely_benign (0.10) | -6.53 | chr4-120062077-G-A |
| 94 | S→* | stop_gained | gnomAD | — | 6.85e-07 | LoF | — | — | chr4-120062077-G-C |
| 94 | S→L | missense_variant | COSMIC | — | — | — | likely_benign (0.10) | -6.53 | COSV56636668 |
| 96 | Q→R | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_benign (0.32) | -8.62 | chr4-120062071-T-C |
| 96 | Q→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636702 |
| 98 | L→L | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120062064-C-A |
| 98 | L→L | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637689 |
| 99 | V→V | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120062061-A-T |
| 99 | V→F | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.99) | -12.31 | chr4-120062063-C-A |
| 100 | V→L | missense_variant | gnomAD | — | 6.85e-07 | — | likely_benign (0.27) | -7.25 | chr4-120062060-C-G |
| 100 | V→G | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.92) | -11.81 | COSV106426017 |
| 101 | V→V | synonymous_variant | gnomAD | — | 4.79e-06 | — | — | 0.00 | chr4-120062055-A-G |
| 101 | V→I | missense_variant | gnomAD | — | 6.16e-06 | damaging | likely_benign (0.22) | -8.50 | chr4-120062057-C-T |
| 102 | I→I | synonymous_variant | gnomAD | — | 4.11e-06 | — | — | 0.00 | chr4-120062052-G-A |
| 102 | I→T | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.98) | -8.56 | chr4-120062053-A-G |
| 104 | N→D | missense_variant | gnomAD | — | 6.16e-06 | — | likely_benign (0.07) | -6.80 | chr4-120062048-T-C |
| 104 | N→D | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.07) | -6.80 | ClinVar:3121965 |
| 105 | I→V | missense_variant | gnomAD | — | 6.09e-05 | — | likely_benign (0.06) | -4.88 | chr4-120062045-T-C |
| 105 | I→N | missense_variant | COSMIC | — | — | damaging | likely_benign (0.31) | -8.57 | COSV56636977 |
| 105 | I→V | missense_variant | COSMIC | — | — | — | likely_benign (0.06) | -4.88 | COSV99047961 |
| 107 | S→R | missense_variant | gnomAD | — | 6.85e-07 | damaging | ambiguous (0.48) | -9.10 | chr4-120062037-A-C |
| 107 | S→S | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120062037-A-G |
| 107 | S→T | missense_variant | gnomAD | — | 6.85e-07 | — | likely_benign (0.06) | -3.75 | chr4-120062038-C-G |
| 107 | S→N | missense_variant | gnomAD | — | 1.16e-05 | — | likely_benign (0.07) | -5.35 | chr4-120062038-C-T |
| 107 | S→R | missense_variant | COSMIC | — | — | damaging | ambiguous (0.48) | -9.10 | COSV56636802 |
| 108 | G→V | missense_variant | gnomAD | — | 6.85e-07 | damaging | ambiguous (0.40) | -10.24 | chr4-120062035-C-A |
| 108 | G→D | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_benign (0.21) | -8.74 | chr4-120062035-C-T |
| 109 | E→K | missense_variant | gnomAD | — | 1.44e-05 | damaging | likely_benign (0.33) | -9.75 | chr4-120062033-C-T |
| 109 | E→K | missense_variant | COSMIC | — | — | damaging | likely_benign (0.33) | -9.75 | COSV105174397 |
| 110 | V→V | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120062028-G-A |
| 111 | L→L | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120062025-C-T |
| 111 | L→V | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_benign (0.15) | -8.75 | chr4-120062027-G-C |
| 113 | R→I | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.99) | -13.75 | chr4-120062020-C-A |
| 115 | Q→R | missense_variant | gnomAD | — | 2.74e-06 | damaging | likely_pathogenic (0.85) | -10.81 | chr4-120062014-T-C |
| 115 | Q→P | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.99) | -12.12 | chr4-120062014-T-G |
| 116 | F→L | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (1.00) | -10.44 | chr4-120062012-A-G |
| 117 | D→V | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.81) | -10.75 | chr4-120062008-T-A |
| 117 | D→N | missense_variant | COSMIC | — | — | damaging | ambiguous (0.38) | -9.00 | COSV109419265 |
| 118 | I→I | synonymous_variant | gnomAD | — | 4.11e-06 | — | — | 0.00 | chr4-120062004-A-T |
| 118 | I→T | missense_variant | gnomAD | — | 3.42e-06 | damaging | likely_pathogenic (0.79) | -9.06 | chr4-120062005-A-G |
| 119 | E→Q | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_benign (0.18) | -7.62 | chr4-120062003-C-G |
| 120 | C→Y | missense_variant | gnomAD | — | 2.74e-06 | damaging | likely_pathogenic (0.82) | -9.50 | chr4-120061999-C-T |
| 121 | D→E | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (0.61) | -8.56 | chr4-120061995-G-C |
| 122 | K→M | missense_variant | COSMIC | — | — | damaging | ambiguous (0.41) | -9.25 | COSV56637840 |
| 123 | T→T | synonymous_variant | gnomAD | — | 1.24e-05 | — | — | 0.00 | chr4-120061989-A-G |
| 123 | T→T | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637816 |
| 124 | A→A | synonymous_variant | gnomAD | — | 6.88e-07 | — | — | 0.00 | chr4-120061986-T-G |
| 124 | A→V | missense_variant | gnomAD | — | 6.89e-07 | — | likely_benign (0.10) | -5.11 | chr4-120061987-G-A |
| 124 | A→S | missense_variant | gnomAD | — | 2.07e-06 | — | likely_benign (0.12) | -7.11 | chr4-120061988-C-A |
| 124 | A→V | missense_variant | COSMIC | — | — | — | likely_benign (0.10) | -5.11 | COSV56636463 |
| 125 | K→E | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_benign (0.13) | -7.83 | chr4-120061985-T-C |
| 126 | D→D | synonymous_variant | gnomAD | — | 6.90e-07 | — | — | 0.00 | chr4-120061980-A-G |
| 126 | D→Y | missense_variant | gnomAD | — | 3.45e-06 | damaging | likely_benign (0.26) | -8.36 | chr4-120061982-C-A |
| 127 | D→Y | missense_variant | gnomAD | — | 6.90e-07 | damaging | likely_benign (0.19) | -7.57 | chr4-120061979-C-A |
| 128 | S→S | synonymous_variant | gnomAD | — | 5.60e-06 | — | — | 0.00 | chr4-120060977-A-G |
| 128 | S→I | missense_variant | ClinVar | — | — | damaging | likely_benign (0.15) | -7.89 | ClinVar:4301842 |
| 128 | S→N | missense_variant | COSMIC | — | — | — | likely_benign (0.12) | -5.11 | COSV105174411 |
| 129 | A→A | synonymous_variant | gnomAD | — | 1.39e-06 | — | — | 0.00 | chr4-120060974-T-C |
| 129 | A→V | missense_variant | gnomAD | — | 2.79e-06 | — | likely_benign (0.07) | -3.28 | chr4-120060975-G-A |
| 129 | A→A | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56636648 |
| 130 | P→L | missense_variant | gnomAD | — | 2.08e-06 | — | likely_benign (0.25) | -6.75 | chr4-120060972-G-A |
| 130 | P→A | missense_variant | gnomAD | — | 1.39e-06 | damaging | likely_benign (0.13) | -7.56 | chr4-120060973-G-C |
| 130 | P→T | missense_variant | COSMIC | — | — | damaging | likely_benign (0.21) | -7.84 | COSV99633915 |
| 131 | R→S | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.92) | -8.87 | chr4-120060968-T-A |
| 131 | R→I | missense_variant | gnomAD | — | 6.92e-07 | damaging | likely_pathogenic (0.76) | -10.80 | chr4-120060969-C-A |
| 131 | R→G | missense_variant | gnomAD | — | 2.07e-06 | damaging | likely_pathogenic (0.70) | -7.90 | chr4-120060970-T-C |
| 133 | K→K | synonymous_variant | gnomAD | — | 6.87e-07 | — | — | 0.00 | chr4-120060962-C-T |
| 133 | — | frameshift_variant | gnomAD | — | 6.87e-07 | LoF | — | — | chr4-120060962-CT-C |
| 133 | K→M | missense_variant | gnomAD | — | 1.99e-05 | damaging | likely_pathogenic (0.82) | -10.31 | chr4-120060963-T-A |
| 133 | K→E | missense_variant | gnomAD | — | 6.88e-07 | damaging | likely_pathogenic (0.96) | -11.06 | chr4-120060964-T-C |
| 134 | S→S | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120060959-A-G |
| 134 | S→F | missense_variant | gnomAD | — | 5.70e-05 | damaging | likely_pathogenic (0.80) | -9.05 | chr4-120060960-G-A |
| 134 | S→C | missense_variant | gnomAD | — | 1.37e-06 | — | likely_benign (0.21) | -7.18 | chr4-120060960-G-C |
| 134 | S→C | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.21) | -7.18 | ClinVar:2624283 |
| 135 | Q→H | missense_variant | gnomAD | — | 2.06e-06 | — | likely_benign (0.21) | -6.53 | chr4-120060956-C-G |
| 135 | Q→P | missense_variant | gnomAD | — | 3.29e-05 | — | likely_benign (0.10) | -7.21 | chr4-120060957-T-G |
| 136 | K→K | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120060953-T-C |
| 136 | K→T | missense_variant | gnomAD | — | 6.86e-07 | damaging | ambiguous (0.37) | -8.37 | chr4-120060954-T-G |
| 136 | K→E | missense_variant | gnomAD | — | 6.86e-07 | damaging | ambiguous (0.42) | -7.78 | chr4-120060955-T-C |
| 139 | Q→R | missense_variant | gnomAD | — | 3.43e-06 | damaging | likely_benign (0.30) | -9.00 | chr4-120060945-T-C |
| 139 | Q→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV99633770 |
| 140 | D→N | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_benign (0.15) | -8.18 | chr4-120060943-C-T |
| 140 | D→N | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_benign (0.15) | -8.18 | ClinVar:3121966 |
| 142 | I→V | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (0.65) | -9.37 | chr4-120060937-T-C |
| 142 | I→I | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637007 |
| 142 | I→V | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.65) | -9.37 | COSV56636872 |
| 143 | R→L | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (0.96) | -10.50 | chr4-120060933-C-A |
| 143 | R→H | missense_variant | gnomAD | — | 6.85e-06 | damaging | likely_pathogenic (0.74) | -8.75 | chr4-120060933-C-T |
| 143 | R→C | missense_variant | gnomAD | — | 3.43e-05 | damaging | likely_pathogenic (0.61) | -8.56 | chr4-120060934-G-A |
| 143 | R→G | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.86) | -10.06 | chr4-120060934-G-C |
| 143 | R→S | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.93) | -9.37 | chr4-120060934-G-T |
| 143 | R→C | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.61) | -8.56 | COSV99633932 |
| 144 | S→A | missense_variant | gnomAD | — | 6.85e-07 | — | likely_benign (0.12) | -6.47 | chr4-120060931-A-C |
| 144 | S→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56636444 |
| 145 | V→V | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060926-C-G |
| 146 | I→M | missense_variant | gnomAD | — | 8.22e-06 | damaging | likely_benign (0.27) | -8.94 | chr4-120060923-G-C |
| 147 | R→K | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.79) | -10.37 | COSV56637106 |
| 147 | R→T | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (1.00) | -13.44 | COSV56636656 |
| 148 | Q→Q | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637581 |
| 150 | T→T | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120060911-T-C |
| 150 | T→I | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.94) | -9.81 | COSV56637834 |
| 151 | A→A | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120060908-A-C |
| 151 | A→D | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (1.00) | -11.12 | COSV56637574 |
| 152 | T→T | synonymous_variant | gnomAD | — | 1.10e-05 | — | — | 0.00 | chr4-120060905-C-T |
| 152 | T→M | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (0.69) | -9.56 | chr4-120060906-G-A |
| 152 | T→T | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637199 |
| 152 | T→M | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.69) | -9.56 | COSV99633752 |
| 153 | V→V | synonymous_variant | gnomAD | — | 6.87e-07 | — | — | 0.00 | chr4-120060902-C-T |
| 153 | V→V | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56637231 |
| 153 | V→A | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.97) | -10.50 | COSV56637826 |
| 157 | P→P | synonymous_variant | gnomAD | — | 6.18e-02 | — | — | 0.00 | chr4-120060890-T-C |
| 157 | P→L | missense_variant | gnomAD | — | 6.89e-07 | damaging | likely_pathogenic (0.99) | -11.69 | chr4-120060891-G-A |
| 157 | P→P | synonymous_variant | COSMIC | — | — | — | — | 0.00 | COSV56636944 |
| 158 | L→L | synonymous_variant | gnomAD | — | 6.89e-07 | — | — | 0.00 | chr4-120060887-C-G |
| 160 | E→D | missense_variant | COSMIC | — | — | — | likely_benign (0.09) | -6.00 | COSV56637746 |
| 160 | E→Q | missense_variant | COSMIC | — | — | damaging | likely_benign (0.34) | -8.68 | COSV56636515 |
| 161 | V→A | missense_variant | gnomAD | — | 6.91e-07 | — | likely_benign (0.09) | -3.35 | chr4-120060879-A-G |
| 161 | V→F | missense_variant | gnomAD | — | 6.91e-07 | damaging | likely_benign (0.17) | -8.22 | chr4-120060880-C-A |
| 162 | S→F | missense_variant | gnomAD | — | 6.92e-07 | damaging | likely_benign (0.33) | -8.87 | chr4-120060876-G-A |
| 162 | S→Y | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_benign (0.29) | -9.62 | chr4-120060876-G-T |
| 162 | — | frameshift_variant | gnomAD | — | 6.92e-07 | LoF | — | — | chr4-120060876-GA-G |
| 163 | C→Y | missense_variant | gnomAD | — | 3.45e-06 | damaging | likely_pathogenic (0.97) | -10.19 | chr4-120060290-C-T |
| 163 | C→Y | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_pathogenic (0.97) | -10.19 | ClinVar:4050418 |
| 163 | C→R | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.98) | -11.37 | COSV56637100 |
| 164 | S→L | missense_variant | gnomAD | — | 6.88e-07 | damaging | ambiguous (0.39) | -9.55 | chr4-120060287-G-A |
| 164 | S→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV56637188 |
| 166 | D→E | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.91) | -8.31 | chr4-120060280-A-T |
| 166 | D→N | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.70) | -9.06 | COSV108814783 |
| 167 | L→L | synonymous_variant | gnomAD | — | 2.06e-06 | — | — | 0.00 | chr4-120060277-C-T |
| 167 | L→P | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (1.00) | -11.37 | chr4-120060278-A-G |
| 168 | L→L | synonymous_variant | gnomAD | — | 2.06e-05 | — | — | 0.00 | chr4-120060274-C-T |
| 168 | L→V | missense_variant | gnomAD | — | 2.06e-06 | damaging | likely_pathogenic (0.82) | -9.62 | chr4-120060276-G-C |
| 169 | — | frameshift_variant | COSMIC | — | — | LoF | — | — | COSV99633904 |
| 170 | Y→D | missense_variant | gnomAD | — | 6.86e-07 | damaging | likely_pathogenic (0.99) | -11.12 | chr4-120060270-A-C |
| 171 | T→I | missense_variant | gnomAD | — | 6.86e-07 | damaging | likely_pathogenic (0.96) | -6.87 | chr4-120060266-G-A |
| 171 | T→A | missense_variant | gnomAD | — | 6.85e-07 | — | ambiguous (0.36) | -6.75 | chr4-120060267-T-C |
| 171 | T→A | missense_variant | COSMIC | — | — | — | ambiguous (0.36) | -6.75 | COSV56637751 |
| 173 | — | frameshift_variant | gnomAD | — | 4.11e-06 | LoF | — | — | chr4-120060260-TTGTC-T |
| 174 | D→H | missense_variant | gnomAD | — | 4.11e-06 | damaging | likely_pathogenic (0.68) | -8.75 | chr4-120060258-C-G |
| 175 | L→F | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_benign (0.33) | -8.37 | chr4-120060253-C-G |
| 175 | L→S | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_benign (0.29) | -8.87 | chr4-120060254-A-G |
| 175 | L→M | missense_variant | gnomAD | — | 2.05e-06 | — | likely_benign (0.10) | -7.28 | chr4-120060255-A-T |
| 175 | L→F | missense_variant | COSMIC | — | — | damaging | likely_benign (0.33) | -8.37 | COSV99633667 |
| 175 | L→W | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.59) | -11.50 | COSV56636532 |
| 176 | V→V | synonymous_variant | gnomAD | — | 6.84e-07 | — | — | 0.00 | chr4-120060250-A-T |
| 176 | V→L | missense_variant | gnomAD | — | 7.53e-06 | — | likely_benign (0.11) | -5.09 | chr4-120060252-C-G |
| 177 | V→V | synonymous_variant | gnomAD | — | 4.79e-06 | — | — | 0.00 | chr4-120060247-T-C |
| 177 | V→L | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.61) | -8.00 | chr4-120060249-C-A |
| 179 | — | frameshift_variant | COSMIC | — | — | LoF | — | — | COSV56637918 |
| 179 | — | frameshift_variant | COSMIC | — | — | LoF | — | — | COSV56637019 |
| 179 | E→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV99633990 |
| 181 | W→S | missense_variant | gnomAD | — | 6.84e-07 | damaging | likely_pathogenic (1.00) | -12.37 | chr4-120060236-C-G |
| 181 | W→G | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.98) | -11.81 | COSV56637715 |
| 182 | E→K | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.75) | -9.25 | COSV99633670 |
| 183 | E→K | missense_variant | gnomAD | — | 2.74e-06 | damaging | likely_pathogenic (0.92) | -9.69 | chr4-120060231-C-T |
| 184 | S→S | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060226-C-A |
| 184 | S→S | synonymous_variant | gnomAD | — | 1.57e-05 | — | — | 0.00 | chr4-120060226-C-T |
| 184 | S→L | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.69) | -10.25 | COSV104613725 |
| 185 | G→E | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.89) | -9.12 | chr4-120060224-C-T |
| 186 | — | frameshift_variant | gnomAD | — | 6.85e-07 | LoF | — | — | chr4-120060220-TG-T |
| 186 | P→T | missense_variant | gnomAD | — | 9.58e-06 | damaging | likely_pathogenic (0.89) | -10.31 | chr4-120060222-G-T |
| 186 | P→T | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.89) | -10.31 | COSV56637625 |
| 188 | F→L | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.77) | -6.34 | chr4-120060216-A-G |
| 189 | I→I | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060211-A-T |
| 189 | I→V | missense_variant | gnomAD | — | 4.11e-06 | — | likely_benign (0.13) | -6.56 | chr4-120060213-T-C |
| 190 | T→T | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060208-G-A |
| 190 | T→T | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060208-G-C |
| 191 | N→N | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060205-A-G |
| 191 | N→S | missense_variant | gnomAD | — | 6.85e-07 | — | likely_benign (0.07) | -4.55 | chr4-120060206-T-C |
| 192 | S→F | missense_variant | gnomAD | — | 3.42e-06 | damaging | likely_pathogenic (0.85) | -10.37 | chr4-120060203-G-A |
| 192 | S→A | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_benign (0.10) | -9.31 | chr4-120060204-A-C |
| 192 | S→T | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_benign (0.33) | -10.69 | chr4-120060204-A-T |
| 193 | E→G | missense_variant | gnomAD | — | 1.51e-05 | damaging | likely_pathogenic (0.86) | -10.19 | chr4-120060200-T-C |
| 194 | E→G | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.73) | -9.69 | chr4-120060197-T-C |
| 194 | E→K | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.73) | -9.00 | chr4-120060198-C-T |
| 195 | V→I | missense_variant | gnomAD | — | 6.85e-07 | damaging | ambiguous (0.49) | -9.00 | chr4-120060195-C-T |
| 196 | R→L | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.76) | -8.18 | chr4-120060191-C-A |
| 196 | R→H | missense_variant | gnomAD | — | 7.53e-06 | — | likely_benign (0.32) | -6.15 | chr4-120060191-C-T |
| 196 | R→C | missense_variant | gnomAD | — | 1.64e-05 | — | ambiguous (0.44) | -6.15 | chr4-120060192-G-A |
| 196 | R→L | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.76) | -8.18 | COSV99633797 |
| 196 | R→C | missense_variant | COSMIC | — | — | — | ambiguous (0.44) | -6.15 | COSV56637784 |
| 197 | L→F | missense_variant | gnomAD | — | 1.10e-05 | damaging | likely_pathogenic (0.90) | -9.69 | chr4-120060189-G-A |
| 197 | L→R | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.99) | -13.06 | COSV99633921 |
| 198 | R→L | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.97) | -10.50 | chr4-120060185-C-A |
| 198 | R→H | missense_variant | gnomAD | — | 7.53e-06 | damaging | likely_pathogenic (0.71) | -8.25 | chr4-120060185-C-T |
| 198 | R→C | missense_variant | gnomAD | — | 2.74e-06 | damaging | likely_pathogenic (0.86) | -8.19 | chr4-120060186-G-A |
| 198 | R→H | missense_variant | ClinVar | Uncertain significance | — | damaging | likely_pathogenic (0.71) | -8.25 | ClinVar:3541917 |
| 198 | R→C | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.86) | -8.19 | COSV56637566 |
| 199 | S→S | synonymous_variant | gnomAD | — | 9.59e-06 | — | — | 0.00 | chr4-120060181-T-C |
| 199 | S→L | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.86) | -12.12 | chr4-120060182-G-A |
| 199 | S→* | stop_gained | COSMIC | — | — | LoF | — | — | COSV99633830 |
| 200 | F→F | synonymous_variant | gnomAD | — | 6.85e-07 | — | — | 0.00 | chr4-120060178-A-G |
| 200 | F→L | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (1.00) | -9.62 | chr4-120060180-A-G |
| 203 | T→I | missense_variant | gnomAD | — | 6.85e-07 | damaging | likely_pathogenic (0.89) | -7.96 | chr4-120060170-G-A |
| 203 | T→I | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.89) | -7.96 | COSV106096082 |
| 204 | I→V | missense_variant | gnomAD | — | 5.62e-03 | — | likely_benign (0.10) | -5.18 | chr4-120060168-T-C |
| 204 | I→V | missense_variant | ClinVar | Benign | — | — | likely_benign (0.10) | -5.18 | ClinVar:782943 |
| 205 | H→H | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120060163-G-A |
| 205 | H→R | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (0.99) | -11.31 | COSV56637130 |
| 207 | V→V | synonymous_variant | gnomAD | — | 6.86e-07 | — | — | 0.00 | chr4-120060157-T-C |
| 208 | N→N | synonymous_variant | gnomAD | — | 1.37e-06 | — | — | 0.00 | chr4-120060154-A-G |
| 209 | S→N | missense_variant | gnomAD | — | 1.37e-06 | damaging | likely_pathogenic (0.93) | -10.75 | chr4-120060152-C-T |
| 209 | S→G | missense_variant | COSMIC | — | — | damaging | likely_benign (0.28) | -9.44 | COSV56636733 |
| 210 | M→K | missense_variant | gnomAD | — | 7.56e-06 | damaging | ambiguous (0.44) | -9.44 | chr4-120060149-A-T |
| 211 | V→M | missense_variant | COSMIC | — | — | damaging | likely_pathogenic (1.00) | -11.62 | COSV56636857 |
| 212 | A→A | synonymous_variant | gnomAD | — | 2.07e-06 | — | — | 0.00 | chr4-120060142-G-A |
| 212 | A→A | synonymous_variant | gnomAD | — | 6.91e-07 | — | — | 0.00 | chr4-120060142-G-C |
| 212 | A→V | missense_variant | gnomAD | — | 6.91e-07 | damaging | likely_pathogenic (0.78) | -8.25 | chr4-120060143-G-A |
| 212 | A→T | missense_variant | gnomAD | — | 2.07e-06 | — | ambiguous (0.42) | -6.56 | chr4-120060144-C-T |
| 213 | Y→Y | synonymous_variant | gnomAD | — | 6.90e-07 | — | — | 0.00 | chr4-120060139-G-A |
| 214 | K→R | missense_variant | gnomAD | — | 2.07e-06 | — | likely_benign (0.06) | -5.31 | chr4-120060137-T-C |
| 214 | K→E | missense_variant | gnomAD | — | 6.90e-07 | damaging | likely_pathogenic (0.69) | -11.37 | chr4-120060138-T-C |
| 215 | I→M | missense_variant | gnomAD | — | 2.07e-06 | — | likely_benign (0.09) | -6.84 | chr4-120060133-A-C |
| 215 | I→I | synonymous_variant | gnomAD | — | 6.90e-07 | — | — | 0.00 | chr4-120060133-A-G |
| 216 | P→S | missense_variant | COSMIC | — | — | — | likely_benign (0.13) | -5.24 | COSV56636813 |
| 217 | V→V | synonymous_variant | gnomAD | — | 6.91e-07 | — | — | 0.00 | chr4-120060127-G-A |
| 217 | V→L | missense_variant | gnomAD | — | 4.15e-06 | — | likely_benign (0.09) | -5.62 | chr4-120060129-C-G |
| 217 | V→I | missense_variant | gnomAD | — | 4.84e-06 | — | likely_benign (0.07) | -4.18 | chr4-120060129-C-T |
| 217 | V→I | missense_variant | COSMIC | — | — | — | likely_benign (0.07) | -4.18 | COSV56636962 |
| 218 | N→S | missense_variant | gnomAD | — | 1.38e-06 | — | likely_benign (0.06) | -3.94 | chr4-120060125-T-C |
| 219 | D→D | synonymous_variant | gnomAD | — | 1.38e-05 | — | — | 0.00 | chr4-120060121-G-A |
| 219 | D→Y | missense_variant | gnomAD | — | 1.38e-06 | damaging | likely_benign (0.28) | -7.90 | chr4-120060123-C-A |
| 219 | D→N | missense_variant | gnomAD | — | 2.77e-06 | — | likely_benign (0.08) | -6.37 | chr4-120060123-C-T |
| 219 | D→N | missense_variant | ClinVar | Uncertain significance | — | — | likely_benign (0.08) | -6.37 | ClinVar:2539636 |
390 variants in the shared canonical core.
LoF = frameshift / stop-gain / splice-disrupting — inherently loss-of-function, flagged by consequence (AlphaMissense and ESM-C score only missense/substitutions, so they are blank here by design, not by absence of impact). AlphaMissense is computed in the canonical reading frame, so it scores the shared core but reads N/A across an isoform-unique extension — use ESM-C ΔLLR there.