SwissIsoform v2

CBX1 · ENST00000225603.9

EXTENDED 226 aa (canonical 185 aa) · UniProt P83916 · CDLMPS

chr17:48101353:-:CTG:ENST00000225603.9

AI summary A confidently-folded but structurally unmoored 42-aa N-terminal extension is added ahead of the HP1-beta chromoshadow/chromo core, with no domain or localization change.
How it diverges

The extension folds into a discrete strand element (pLDDT ~0.80) yet forms almost no contacts with the canonical CBX1 body and sits at very high inter-region PAE, meaning it is a locally structured appendage rather than an integrated addition to HP1-beta's chromodomain/chromoshadow architecture. The large shared-region RMSD is not trustworthy as a core refold given the low global pTM, so it should not be read as CBX1's H3K9me-reading fold being reorganized. Separately, a modest whole-protein biophysical shift (charge/hydropathy) and an SAE feature-magnitude shift indicate the extension has a detectable but non-domain-forming compositional signature.

Why it matters

CBX1/HP1-beta's core function depends on its chromodomain reading H3K9me3 and its chromoshadow domain mediating dimerization/partner recruitment (SUV39H1, PurB/Sp3, KAP-1); since S1 finds no real InterPro domain gained or lost in the added region, this extension does not appear to add or remove a functional module, and DeepLoc still calls both isoform and canonical nuclear at a calibrated, confident baseline, so nuclear/chromatin targeting is not disrupted. The unmoored, low-confidence nature of the extension's fold placement makes it unlikely to meaningfully engage or block the reader/adaptor functions central to CBX1's known heterochromatin and DNA-damage-response roles, though a subtle biophysical/representational change at the N-terminus cannot be ruled out.

Structured N-terminal extensionBiophysical shiftInterpretable-feature shift
LLM confidence low

The P2 shared-region RMSD (14.72 Å) is not trustworthy given low pTM (~0.35-0.39) and high inter-region PAE, so no core-refold claim is made; the extension's fold-confidence (P1) is real but its structural integration with the canonical body is unresolved, and mass-spec could not validate any unique peptide from this extension.

Folding

Canonical (185 aa)
Download CIF
Isoform (226 aa)
Download CIF
Coloured by ESMFold2 pLDDT confidence (blue = high, orange/red = low). Differential region — residues 1–41 (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 (1–41).

Evidence — click any tile for the differential-region detail

C Conservation Interesting
LLM reasoning
The N-terminal extension this isoform adds ahead of the canonical CBX1 start is itself under purifying selection, not just passively conserved sequence in a UTR-like region. Amino-acid identity across primates is high (95.4%) though slightly below the canonical baseline (99.5%), and mammalian identity remains substantial (88.4%, versus 97.8% for canonical) with the reading frame intact in under half of mammals — expected given the depth of the comparison but still indicating a functionally maintained frame rather than a drifting ORF. Most decisive is the absolute phyloP signal over the unique region itself: mean 3.29, well above the ~2 threshold for strong constraint, and even the Kozak/TIS context shows phyloP >1.9-2.3, suggesting selection acting directly on this added coding sequence and its start site. Together these argue the extension is a real, evolutionarily maintained coding addition rather than incidental upstream sequence.
Unique region 95.4% similar across primates
Unique region 88.4% similar across mammals
Unique region PhyloP: 3.29 — purifying selection
D Detection Interesting
LLM reasoning
This alternative TIS is genuinely and reproducibly used in vivo: it is detected in 5 of 6 cell lines with strong statistical support (e.g. K562 fisher q=2.5e-12, HeLa p=4.8e-4), and start-site usage reaches a max initiation efficiency of 0.095, well above the 0.01 threshold, indicating this upstream start codon is actively and efficiently recognized by ribosomes rather than being a rare or noisy event. The one gap is proteomic confirmation of the novel N-terminal extension itself: all 10 isoform-unique peptides covering the added 42-aa N-terminal segment (e.g. MGATPPGDPTR, ASSAAPIPLGLLGAALSSVTLYTR) failed PepQuery2 validation, so mass spec offers no direct peptide-level confirmation of the extended protein product. Still, the ribosome-profiling evidence for reproducible, efficient initiation at this upstream CTG across multiple cell lines is strong and biologically meaningful on its own, supporting that this extended isoform is a real, actively translated alternative start event even though it has not yet been corroborated by unique peptide detection.
detected in 5/6 cell lines
Max Initiation Efficiency: 0.0945
0/10 isoform-unique peptides validated
L Localization Not interesting
LLM reasoning
The N-terminal extension does not alter predicted subcellular fate: both isoform and canonical protein are called Nucleus by DeepLoc (though top-class probability drops modestly from 0.927 to 0.853), both retain the same nuclear localization signal annotation, and both remain soluble/non-membrane-associated. Sorting-signal predictions are likewise unchanged - neither canonical nor isoform shows a signal peptide (SignalP: OTHER for both) or a transit peptide (TargetP: noTP for both), with only negligible probability shifts (delta -0.038 overall, +0.030 for secretory, +0.009 for mitochondrial). No evidence here supports a functional consequence of the added 42-aa N-terminal segment for localization or targeting.
iso: Nucleus | canon: Nucleus
iso: noTP | canon: noTP
M Mutation Landscape Not interesting
LLM reasoning
This is an N-terminal extension whose unique region was previously 5'UTR/intronic sequence, so the germline-constraint signals (gnomAD depletion ratio, ESM-C enrichment) are uninterpretable by construction and cannot be read as evidence of protein constraint. That leaves disease-variant density as the only assessable member, and it is quiet: zero ClinVar pathogenic variants exist anywhere on this isoform (unique or shared region, confirmed by direct query, n_matched=0), the unique-region disease count is only 4 (vs 89 in the shared core, enrichment ratio 0.20 — depleted, not enriched), and a full-isoform positional histogram shows a diffuse spread across 172 distinct residues with just 14.7% of all 353 variants falling on the ten busiest positions — no tight hotspot anywhere, including at the alternative start codon, where the only variants present are low-frequency gnomAD entries annotated as intronic. There is no clustering, no pathogenic burden, and no start-codon-disrupting signal to flag.
gnomAD variants 1.60× more in unique region — tolerant
Disease variants 4.93× less in unique region — depleted
P Predicted Structure Not interesting
LLM reasoning
The extension contains a locally well-folded 22-residue strand (residues 7-28, pLDDT ~0.76-0.90) but it is essentially disconnected from the rest of the protein: PAE between this strand and the remainder of the isoform (residues 42-226) averages 30.5 Å, and the whole extension (1-42) makes only 3 Ca contacts with the downstream body, clustered right at the boundary (residues 43-44) rather than forming a real interface. This is a confidently-folded fragment dangling in an unresolved orientation, not an integrated structural element. The large shared-core RMSD (14.72 Å) cannot be read as a genuine refold either, since global pTM is only 0.35 (isoform) / 0.39 (canonical) and body-vs-body PAE averages 18.17 Å with a max of 31.4 Å — the whole prediction is low-confidence, so the RMSD is placement uncertainty, not evidence of core reorganization. Taken together, no submodule here supports a credible functional or structural signal for this extension.
pLDDT Differential Region: 0.76
Shared-Region RMSD: 14.72 Å
1 secondary structure identified in unique region
S Structural Characteristics Interesting
LLM reasoning
The added N-terminal extension shifts the whole protein's biophysical character measurably, with fraction-charged differing enough to fire the whole-protein delta (delta -0.061, alongside a gravy delta of +0.263), even though no real InterPro domain is gained or lost by the added segment. The ESM-C sparse-feature check corroborates this at the magnitude level: the strongest shared-feature activation shift is 11.73, above the 10.0 threshold, indicating the extension measurably perturbs the model's internal representation of the protein beyond simple composition noise (feature counts and labels themselves are not being used as evidence here). Together these argue the extension is not inert sequence padding but introduces a distinct biophysical/representational signature at the N-terminus, even though it does not overlap any annotated folded domain.
No diverging domains
more hydrophobic (+1.45) · less charged (-0.34) · less disordered (-0.09)
149 SAE features differ

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 L→L synonymous_variant gnomAD — 1.20e-05 — N/A — chr17-48101351-C-G
1 G→G synonymous_variant gnomAD — 2.40e-06 — N/A 0.00 chr17-48101348-G-A
1 G→G synonymous_variant gnomAD — 3.60e-06 — N/A 0.00 chr17-48101348-G-T
1 — frameshift_variant gnomAD — 2.40e-06 LoF — — chr17-48101348-GC-G
1 G→R missense_variant gnomAD — 1.20e-06 — N/A 0.22 chr17-48101350-C-G
2 A→D missense_variant gnomAD — 3.60e-06 — N/A -1.59 chr17-48101346-G-T
2 A→S missense_variant gnomAD — 6.00e-06 — N/A -0.66 chr17-48101347-C-A
2 A→T missense_variant gnomAD — 7.08e-05 — N/A -0.92 chr17-48101347-C-T
3 T→N missense_variant gnomAD — 1.20e-06 — N/A -1.44 chr17-48101343-G-T
4 P→P synonymous_variant gnomAD — 2.40e-06 — N/A 0.00 chr17-48101339-G-T
4 P→T missense_variant gnomAD — 1.20e-06 — N/A -1.11 chr17-48101341-G-T
5 P→S missense_variant gnomAD — 1.20e-06 — N/A -0.39 chr17-48101338-G-A
6 G→S missense_variant gnomAD — 1.20e-06 — N/A -0.14 chr17-48101335-C-T
8 P→P synonymous_variant gnomAD — 2.40e-06 — N/A 0.00 chr17-48101327-C-G
8 P→P synonymous_variant gnomAD — 4.80e-06 — N/A 0.00 chr17-48101327-C-T
8 P→Q missense_variant gnomAD — 2.40e-06 — N/A -1.23 chr17-48101328-G-T
9 — frameshift_variant gnomAD — 3.60e-06 LoF — — chr17-48101324-C-CGTCGG
9 T→P missense_variant gnomAD — 4.80e-06 — N/A 1.19 chr17-48101326-T-G
10 R→R synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101321-T-A
12 A→A synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101315-G-A
12 — frameshift_variant gnomAD — 1.20e-06 LoF — — chr17-48101316-G-GCGCGT
12 A→S missense_variant gnomAD — 7.19e-06 — N/A 0.03 chr17-48101317-C-A
12 — frameshift_variant gnomAD — 4.80e-06 LoF — — chr17-48101317-C-CA
13 S→S synonymous_variant gnomAD — 7.89e-01 — N/A 0.00 chr17-48101312-G-A
13 S→R missense_variant gnomAD — 4.08e-05 — N/A 0.45 chr17-48101312-G-C
13 S→T missense_variant gnomAD — 1.14e-04 — N/A -0.98 chr17-48101313-C-G
13 S→N missense_variant gnomAD — 1.20e-06 — N/A -2.05 chr17-48101313-C-T
14 S→S synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101309-G-A
14 S→N missense_variant gnomAD — 7.19e-06 — N/A -2.97 chr17-48101310-C-T
14 S→G missense_variant gnomAD — 1.20e-06 — N/A 0.05 chr17-48101311-T-C
15 A→A synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101306-T-C
15 A→V missense_variant gnomAD — 8.39e-05 — N/A -1.72 chr17-48101307-G-A
15 A→T missense_variant gnomAD — 2.40e-06 — N/A -1.67 chr17-48101308-C-T
16 A→V missense_variant gnomAD — 1.20e-06 — N/A -1.05 chr17-48101304-G-A
17 P→P synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101300-C-A
17 P→L missense_variant gnomAD — 2.04e-05 — N/A -0.31 chr17-48101301-G-A
17 P→R missense_variant gnomAD — 2.40e-06 — N/A 0.12 chr17-48101301-G-C
18 I→V missense_variant gnomAD — 1.20e-06 — N/A 1.38 chr17-48101299-T-C
19 P→L missense_variant gnomAD — 1.20e-06 — N/A -0.57 chr17-48101295-G-A
20 L→L synonymous_variant gnomAD — 9.59e-06 — N/A 0.00 chr17-48101291-G-A
20 L→F missense_variant gnomAD — 1.20e-06 — N/A -1.69 chr17-48101293-G-A
21 G→G synonymous_variant gnomAD — 2.40e-06 — N/A 0.00 chr17-48101288-C-A
21 G→E missense_variant gnomAD — 1.20e-06 — N/A -1.44 chr17-48101289-C-T
21 G→R missense_variant gnomAD — 1.20e-06 — N/A 0.59 chr17-48101290-C-G
22 L→L synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101285-G-A
22 L→L synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101285-G-C
22 L→F missense_variant gnomAD — 2.40e-06 — N/A -1.19 chr17-48101287-G-A
23 L→F missense_variant gnomAD — 7.19e-06 — N/A -1.48 chr17-48101282-C-G
24 G→G synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101279-G-A
25 A→S missense_variant gnomAD — 1.20e-06 — N/A -0.05 chr17-48101278-C-A
25 A→T missense_variant gnomAD — 1.20e-06 — N/A -1.42 chr17-48101278-C-T
27 L→L synonymous_variant gnomAD — 1.20e-06 — N/A 0.00 chr17-48101270-C-T
29 S→S synonymous_variant gnomAD — 4.57e-04 — N/A 0.00 chr17-48077038-G-A
29 S→S synonymous_variant COSMIC — — — N/A 0.00 COSV99848140
30 V→V synonymous_variant gnomAD — 6.91e-07 — N/A 0.00 chr17-48077035-G-C
30 V→I missense_variant gnomAD — 1.52e-05 — N/A -3.78 chr17-48077037-C-T
30 V→I missense_variant COSMIC — — — N/A -3.78 COSV99848059
31 T→T synonymous_variant gnomAD — 2.76e-06 — N/A 0.00 chr17-48077032-G-A
31 T→A missense_variant gnomAD — 6.91e-07 — N/A -3.44 chr17-48077034-T-C
31 — frameshift_variant gnomAD — 6.91e-07 LoF — — chr17-48077034-T-TCA
32 L→V missense_variant gnomAD — 6.91e-07 — N/A -5.82 chr17-48077031-G-C
33 — inframe_insertion gnomAD — 2.06e-06 — N/A — chr17-48077027-T-TAAA
34 T→S missense_variant gnomAD — 6.18e-06 — N/A -0.96 chr17-48077024-G-C
34 T→N missense_variant gnomAD — 6.87e-07 — N/A -3.93 chr17-48077024-G-T
37 L→L synonymous_variant gnomAD — 6.85e-07 — N/A 0.00 chr17-48077016-G-A
37 L→V missense_variant gnomAD — 2.19e-05 — N/A -6.18 chr17-48077016-G-C
38 A→A synonymous_variant gnomAD — 3.70e-05 — N/A 0.00 chr17-48077011-C-T
38 A→V missense_variant gnomAD — 6.85e-07 — N/A -5.89 chr17-48077012-G-A
38 A→V missense_variant COSMIC — — — N/A -5.89 COSV56682161
39 G→G synonymous_variant gnomAD — 6.85e-07 — N/A 0.00 chr17-48077008-G-A
39 G→G synonymous_variant COSMIC — — — N/A 0.00 COSV56681939
40 T→T synonymous_variant gnomAD — 6.85e-07 — N/A 0.00 chr17-48077005-A-G

72 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
41 M→I missense_variant gnomAD — 1.37e-06 damaging — -10.94 chr17-48077002-C-G
41 M→I missense_variant gnomAD — 6.85e-07 damaging — -10.94 chr17-48077002-C-T
41 M→T missense_variant gnomAD — 6.85e-07 damaging — -11.50 chr17-48077003-A-G
41 M→L missense_variant gnomAD — 6.85e-07 damaging — -11.19 chr17-48077004-T-G
41 M→V missense_variant COSMIC — — damaging — -11.44 COSV56682591
42 G→G synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076999-C-A
42 G→V missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.88) -9.25 chr17-48077000-C-A
42 G→W missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.97) -12.31 chr17-48077001-C-A
43 — frameshift_variant COSMIC — — LoF — — COSV56681712
43 — frameshift_variant COSMIC — — LoF — — COSV56681499
44 K→K synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48076993-T-C
45 Q→Q synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076990-T-C
45 Q→K missense_variant COSMIC — — damaging ambiguous (0.37) -10.00 COSV56682149
46 N→K missense_variant gnomAD — 1.85e-05 damaging likely_pathogenic (0.68) -8.87 chr17-48076987-G-C
46 N→K missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.68) -8.87 ClinVar:3827926
47 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.73) -9.94 chr17-48076984-C-G
47 — inframe_deletion gnomAD — 6.84e-07 — — — chr17-48076984-CTTG-C
47 K→Q missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.24) -10.25 chr17-48076986-T-G
48 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.84) -9.87 chr17-48076981-C-A
48 K→R missense_variant gnomAD — 6.84e-07 damaging likely_benign (0.12) -9.06 chr17-48076982-T-C
49 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -9.00 chr17-48076978-T-A
49 — inframe_deletion gnomAD — 1.37e-06 — — — chr17-48076978-TTTC-T
49 K→I missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.56) -11.69 chr17-48076979-T-A
49 K→R missense_variant gnomAD — 9.58e-06 damaging likely_benign (0.12) -8.94 chr17-48076979-T-C
49 K→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48076980-T-A
49 K→E missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.42) -9.69 chr17-48076980-T-C
50 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076975-C-T
50 V→G missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.14) -8.75 chr17-48076976-A-C
50 V→M missense_variant gnomAD — 7.53e-06 damaging likely_benign (0.13) -8.37 chr17-48076977-C-T
50 V→L missense_variant COSMIC — — damaging likely_benign (0.20) -8.06 COSV56682280
53 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076966-C-T
53 V→L missense_variant gnomAD — 2.05e-06 damaging likely_benign (0.30) -7.78 chr17-48076968-C-A
53 V→M missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.24) -8.68 chr17-48076968-C-T
54 L→L synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076963-T-C
55 E→K missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.83) -11.12 chr17-48076962-C-T
56 E→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.62) -9.69 chr17-48076959-C-G
56 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.83) -9.56 COSV56681509
57 E→Q missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.61) -9.81 chr17-48076956-C-G
58 E→E synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076951-T-C
58 E→G missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.77) -9.56 chr17-48076952-T-C
59 E→Q missense_variant COSMIC — — damaging likely_pathogenic (0.95) -11.25 COSV99848313
60 E→E synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076945-T-C
62 V→V synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48076939-C-T
62 V→V synonymous_variant COSMIC — — — — 0.00 COSV99848141
63 V→V synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-A
63 V→V synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-G
64 E→V missense_variant ClinVar — — damaging likely_pathogenic (1.00) -11.31 ClinVar:4423332
65 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -9.37 chr17-48076930-T-A
67 L→L synonymous_variant gnomAD — 6.84e-06 — — 0.00 chr17-48076924-G-A
67 L→I missense_variant COSMIC — — damaging likely_benign (0.28) -9.56 COSV56682110
68 D→H missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.94) -7.89 chr17-48076923-C-G
68 D→N missense_variant gnomAD — 1.85e-05 damaging likely_pathogenic (0.56) -4.01 chr17-48076923-C-T
69 R→H missense_variant gnomAD — 2.74e-06 damaging likely_pathogenic (0.79) -7.03 chr17-48076919-C-T
69 R→C missense_variant gnomAD — 1.23e-05 damaging likely_pathogenic (0.87) -7.12 chr17-48076920-G-A
70 R→Q missense_variant gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -9.25 chr17-48076916-C-T
70 R→R synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076917-G-T
70 R→R synonymous_variant COSMIC — — — — 0.00 COSV56682056
70 R→* stop_gained COSMIC — — LoF — — COSV56681749
71 V→V synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076912-C-T
71 V→A missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -7.43 chr17-48076913-A-G
72 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076909-T-C
72 V→L missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.76) -6.96 chr17-48076911-C-A
73 K→K synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076906-C-T
74 G→G synonymous_variant gnomAD — 3.42e-06 — — 0.00 chr17-48076903-G-A
74 G→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.97 chr17-48076905-C-T
74 G→S missense_variant COSMIC — — damaging likely_pathogenic (0.96) -7.97 COSV99847936
75 K→R missense_variant gnomAD — 2.05e-06 — likely_benign (0.09) -5.18 chr17-48076901-T-C
77 E→D missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -7.72 chr17-48076894-C-G
77 E→K missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.19 COSV56682856
78 Y→Y synonymous_variant gnomAD — 1.71e-05 — — 0.00 chr17-48076891-G-A
79 L→L synonymous_variant gnomAD — 3.43e-06 — — 0.00 chr17-48076888-G-A
79 L→R missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.84) -9.56 chr17-48076889-A-C
79 L→F missense_variant COSMIC — — — ambiguous (0.35) -6.53 COSV56681814
80 L→L synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076885-T-G
81 K→K synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076882-C-T
81 K→E missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -11.19 chr17-48076884-T-C
84 G→G synonymous_variant gnomAD — 4.39e-05 — — 0.00 chr17-48076873-T-C
85 F→F synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076870-G-A
85 F→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV56682209
88 E→K missense_variant gnomAD — 7.10e-07 damaging likely_pathogenic (0.84) -9.50 chr17-48076177-C-T
88 E→Q missense_variant ClinVar — — damaging likely_pathogenic (0.60) -11.12 ClinVar:4423331
88 E→Q missense_variant COSMIC — — damaging likely_pathogenic (0.60) -11.12 COSV56681530
89 D→H missense_variant gnomAD — 7.06e-07 damaging likely_pathogenic (0.97) -12.12 chr17-48076174-C-G
90 N→D missense_variant gnomAD — 1.41e-06 damaging likely_pathogenic (0.97) -10.37 chr17-48076171-T-C
90 N→S missense_variant COSMIC — — damaging likely_pathogenic (0.59) -9.00 COSV56681968
93 E→D missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.56 COSV99848274
95 E→D missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.69 COSV99848151
97 N→N synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076148-G-A
98 L→L synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076147-G-A
101 P→P synonymous_variant gnomAD — 1.51e-05 — — 0.00 chr17-48076136-G-A
101 P→P synonymous_variant gnomAD — 6.88e-07 — — 0.00 chr17-48076136-G-C
101 P→P synonymous_variant COSMIC — — — — 0.00 COSV99847948
102 D→N missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.31 COSV99847954
103 L→L synonymous_variant gnomAD — 1.23e-05 — — 0.00 chr17-48076130-G-A
105 A→A synonymous_variant gnomAD — 5.48e-06 — — 0.00 chr17-48076124-A-G
105 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076124-A-T
105 A→G missense_variant gnomAD — 1.37e-06 damaging ambiguous (0.38) -9.94 chr17-48076125-G-C
108 L→L synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076115-C-T
108 L→L synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076117-G-A
108 L→L synonymous_variant COSMIC — — — — 0.00 COSV105045650
109 Q→* stop_gained COSMIC — — LoF — — COSV99848158
110 S→L missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.27) -9.37 chr17-48076110-G-A
110 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.27) -9.37 ClinVar:4648788
111 Q→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.33) -7.47 chr17-48076107-T-C
111 Q→* stop_gained COSMIC — — LoF — — COSV99848270
112 K→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.12) -6.44 chr17-48076104-T-C
112 K→Q missense_variant ClinVar Uncertain significance — damaging likely_benign (0.33) -8.75 ClinVar:4531663
113 T→A missense_variant gnomAD — 6.85e-07 — likely_benign (0.06) -6.06 chr17-48076102-T-C
115 H→P missense_variant gnomAD — 4.79e-06 — likely_benign (0.11) -7.21 chr17-48076095-T-G
117 T→R missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.23) -7.90 chr17-48076089-G-C
118 D→G missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.27 chr17-48076086-T-C
118 D→N missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.15 chr17-48076087-C-T
118 D→G missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.27 ClinVar:4220041
118 D→N missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.15 ClinVar:4220044
119 K→K synonymous_variant gnomAD — 4.04e-05 — — 0.00 chr17-48076082-T-C
119 K→I missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.43) -10.75 chr17-48076083-T-A
119 K→I missense_variant ClinVar Uncertain significance — damaging ambiguous (0.43) -10.75 ClinVar:4220042
120 S→S synonymous_variant gnomAD — 4.79e-06 — — 0.00 chr17-48076079-T-G
121 E→K missense_variant COSMIC — — damaging likely_benign (0.26) -8.68 COSV99848247
122 G→R missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -8.76 chr17-48076075-C-G
122 G→R missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.76 COSV56682528
125 R→H missense_variant gnomAD — 7.53e-06 damaging likely_pathogenic (0.89) -9.31 chr17-48076065-C-T
125 R→C missense_variant gnomAD — 6.16e-06 damaging likely_pathogenic (0.96) -9.31 chr17-48076066-G-A
125 R→H missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.89) -9.31 ClinVar:2290145
125 R→H missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.31 COSV56682901
125 R→C missense_variant COSMIC — — damaging likely_pathogenic (0.96) -9.31 COSV56682920
126 K→R missense_variant gnomAD — 8.90e-06 damaging likely_benign (0.11) -7.87 chr17-48076062-T-C
127 A→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.08) -6.34 chr17-48076060-C-T
127 A→T missense_variant ClinVar Uncertain significance — — likely_benign (0.08) -6.34 ClinVar:4220043
128 D→G missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.15) -8.36 chr17-48076056-T-C
129 S→A missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.06) -9.87 chr17-48076054-A-C
129 S→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.05) -7.31 chr17-48076054-A-T
133 D→V missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.13) -9.56 chr17-48076041-T-A
133 D→V missense_variant ClinVar Uncertain significance — damaging likely_benign (0.13) -9.56 ClinVar:2307098
133 D→N missense_variant COSMIC — — damaging likely_benign (0.11) -7.93 COSV56682563
134 K→K synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076037-C-T
134 K→R missense_variant gnomAD — 2.05e-06 — likely_benign (0.09) -4.90 chr17-48076038-T-C
134 K→E missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.18) -11.05 chr17-48076039-T-C
134 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682520
134 K→N missense_variant COSMIC — — damaging likely_benign (0.29) -9.30 COSV99848170
135 G→G synonymous_variant gnomAD — 2.06e-06 — — 0.00 chr17-48076034-T-C
135 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48076035-CCCTT-C
135 G→R missense_variant gnomAD — 2.74e-06 damaging ambiguous (0.54) -7.55 chr17-48076036-C-T
136 E→E synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076031-C-T
136 E→Q missense_variant COSMIC — — damaging likely_benign (0.23) -8.62 COSV99848203
137 E→D missense_variant gnomAD — 6.86e-07 — likely_benign (0.05) -5.84 chr17-48076028-C-G
138 S→S synonymous_variant gnomAD — 4.81e-06 — — 0.00 chr17-48076025-G-A
138 S→G missense_variant gnomAD — 6.86e-07 — likely_benign (0.06) -5.94 chr17-48076027-T-C
138 S→S synonymous_variant COSMIC — — — — 0.00 COSV99848275
140 P→P synonymous_variant gnomAD — 2.07e-06 — — 0.00 chr17-48076019-T-C
140 P→L missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -6.30 chr17-48076020-G-A
142 K→N missense_variant gnomAD — 6.90e-07 damaging likely_pathogenic (0.93) -10.37 chr17-48076013-C-A
142 K→K synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076013-C-T
143 K→N missense_variant gnomAD — 6.91e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48076010-C-G
143 K→R missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -5.37 chr17-48076011-T-C
143 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV56681336
143 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV99848297
144 — inframe_deletion gnomAD — 2.77e-06 — — — chr17-48076007-TTTC-T
144 K→R missense_variant gnomAD — 6.92e-07 — likely_benign (0.09) -6.75 chr17-48076008-T-C
145 E→G missense_variant gnomAD — 6.92e-07 damaging likely_benign (0.33) -8.81 chr17-48076005-T-C
146 E→V missense_variant gnomAD — 1.39e-06 damaging likely_benign (0.30) -8.24 chr17-48076002-T-A
146 E→Q missense_variant gnomAD — 6.94e-07 damaging ambiguous (0.43) -8.99 chr17-48076003-C-G
147 S→S synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075098-T-A
147 S→L missense_variant gnomAD — 6.85e-07 — likely_benign (0.08) -6.09 chr17-48075099-G-A
148 E→A missense_variant gnomAD — 6.85e-07 damaging ambiguous (0.50) -9.43 chr17-48075096-T-G
150 P→S missense_variant gnomAD — 6.84e-07 — ambiguous (0.53) -5.76 chr17-48075091-G-A
150 P→Q missense_variant COSMIC — — damaging likely_pathogenic (0.61) -7.20 COSV106082017
150 P→S missense_variant COSMIC — — — ambiguous (0.53) -5.76 COSV56682997
151 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -8.69 chr17-48075087-C-T
151 R→* stop_gained gnomAD — 2.05e-06 LoF — — chr17-48075088-G-A
151 R→* stop_gained COSMIC — — LoF — — COSV56682269
153 F→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.44 chr17-48075081-A-G
154 A→A synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075077-A-C
154 A→A synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075077-A-G
155 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -8.12 chr17-48075075-C-T
155 R→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48075076-G-A
155 R→R synonymous_variant COSMIC — — — — 0.00 COSV107309107
155 R→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV99847942
155 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.99) -8.12 COSV56683114
155 R→* stop_gained COSMIC — — LoF — — COSV104387334
156 G→D missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.62 COSV105045685
158 E→K missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.87) -7.54 chr17-48075067-C-T
158 E→E synonymous_variant COSMIC — — — — 0.00 COSV56681442
159 P→P synonymous_variant gnomAD — 1.97e-04 — — 0.00 chr17-48075062-C-T
159 P→L missense_variant gnomAD — 7.52e-06 damaging likely_pathogenic (1.00) -10.81 chr17-48075063-G-A
159 P→P synonymous_variant COSMIC — — — — 0.00 COSV99848187
159 P→Q missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56682499
159 P→S missense_variant COSMIC — — damaging likely_pathogenic (1.00) -9.69 COSV99848079
160 E→D missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -9.06 chr17-48075059-C-A
160 E→E synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075059-C-T
160 E→D missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.92) -9.06 ClinVar:4648787
160 E→K missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56681862
161 R→R synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075056-C-T
161 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.98) -7.87 COSV56682101
161 R→L missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.12 COSV99848174
162 I→V missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.69 chr17-48075055-T-C
164 G→A missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.44 COSV56682437
166 T→T synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48075041-T-C
168 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075035-G-A
169 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681832
171 E→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -10.00 chr17-48075028-C-G
172 L→L synonymous_variant gnomAD — 9.59e-06 — — 0.00 chr17-48075023-G-A
173 M→L missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48075022-T-A
173 M→V missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.99) -11.50 chr17-48075022-T-C
173 — inframe_deletion COSMIC — — — — — COSV56681204
174 F→F synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075017-G-A
175 L→P missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -13.06 chr17-48075015-A-G
175 L→L synonymous_variant COSMIC — — — — 0.00 COSV99848148
175 L→L synonymous_variant COSMIC — — — — 0.00 COSV56681918
176 M→I missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (0.97) -8.12 chr17-48075011-C-A
176 M→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.81 chr17-48075012-A-G
177 K→K synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48075008-T-C
177 K→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.87 chr17-48075009-T-G
179 K→R missense_variant gnomAD — 8.28e-06 — likely_benign (0.14) -6.94 chr17-48071577-T-C
180 N→K missense_variant COSMIC — — damaging likely_pathogenic (0.89) -8.94 COSV99848229
181 S→F missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.37 COSV56681364
184 A→A synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071561-A-G
185 D→D synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071558-G-A
187 V→L missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.25 chr17-48071554-C-G
189 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071546-G-A
189 A→D missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -12.00 chr17-48071547-G-T
189 A→V missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.62 COSV99848117
191 E→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071542-C-A
191 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.94 COSV56681808
193 N→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.91) -12.44 chr17-48071535-T-C
194 V→F missense_variant gnomAD — 2.74e-06 damaging likely_pathogenic (0.57) -8.73 chr17-48071533-C-A
194 V→V synonymous_variant COSMIC — — — — 0.00 COSV56681933
195 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682664
196 C→C synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071525-G-A
196 C→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -5.97 chr17-48071526-C-G
197 P→L missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.62 chr17-48071523-G-A
198 Q→Q synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071519-C-T
198 Q→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48071521-G-A
199 V→F missense_variant gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -12.05 chr17-48071518-C-A
201 I→I synonymous_variant COSMIC — — — — 0.00 COSV56681722
201 I→T missense_variant COSMIC — — damaging likely_pathogenic (1.00) -11.06 COSV56682067
202 S→S synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48071507-G-T
203 F→F synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071504-G-A
204 Y→Y synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071501-A-G
204 Y→C missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -11.94 chr17-48071502-T-C
207 R→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -11.06 COSV56682552
209 T→T synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071486-C-T
209 T→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -13.94 COSV56681836
211 H→H synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071480-A-G
212 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071477-G-A
212 S→F missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.97) -11.12 chr17-48071478-G-A
212 S→A missense_variant gnomAD — 6.84e-07 damaging likely_benign (0.27) -9.06 chr17-48071479-A-C
212 S→P missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.98) -11.81 chr17-48071479-A-G
212 S→T missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.44) -10.19 chr17-48071479-A-T
213 Y→Y synonymous_variant gnomAD — 2.94e-05 — — 0.00 chr17-48071474-G-A
213 Y→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071474-G-T
214 P→S missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.58) -8.75 chr17-48071473-G-A
214 P→S missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.75 COSV108798400
215 S→S synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071468-C-T
215 S→L missense_variant gnomAD — 2.05e-06 damaging likely_benign (0.21) -8.42 chr17-48071469-G-A
215 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.21) -8.42 ClinVar:3138046
215 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681272
215 S→* stop_gained COSMIC — — LoF — — COSV99848014
216 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.75) -12.00 COSV104555665
217 D→E missense_variant gnomAD — 4.80e-06 — likely_benign (0.09) -5.24 chr17-48071462-A-C
217 D→D synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071462-A-G
217 D→Y missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.71) -11.56 chr17-48071464-C-A
217 D→N missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.31) -10.18 chr17-48071464-C-T
217 D→E missense_variant ClinVar Uncertain significance — — likely_benign (0.09) -5.24 ClinVar:2517719
219 — inframe_deletion gnomAD — 2.06e-06 — — — chr17-48071456-GTCA-G
219 D→N missense_variant COSMIC — — damaging likely_benign (0.19) -8.62 COSV99848218
220 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.72) -9.62 COSV99848111
220 — frameshift_variant COSMIC — — LoF — — COSV56682928
221 K→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071452-T-A
222 D→V missense_variant gnomAD — 6.86e-07 damaging ambiguous (0.45) -9.47 chr17-48071448-T-A
222 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-C-CT
222 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-CTTTT-C
222 D→H missense_variant COSMIC — — damaging likely_pathogenic (0.73) -10.72 COSV56682228
222 D→Y missense_variant COSMIC — — damaging likely_pathogenic (0.65) -9.97 COSV56681987
223 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071445-TC-T
223 D→Y missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.68) -10.43 chr17-48071446-C-A
223 D→N missense_variant gnomAD — 6.86e-07 — likely_benign (0.27) -7.43 chr17-48071446-C-T
223 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071446-CA-C
225 N→K missense_variant gnomAD — 6.87e-07 damaging likely_pathogenic (0.68) -7.21 chr17-48071438-G-C
225 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48071439-TTCTTG-T
225 N→K missense_variant COSMIC — — damaging likely_pathogenic (0.68) -7.21 COSV56682095

281 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.

Evidence