SwissIsoform v2

CBX1 · ENST00000225603.9

TRUNCATED 143 aa (canonical 185 aa) · UniProt P83916 · CDLMPS

chr17:48076878:-:AAG:ENST00000225603.9

AI summary Truncation removes the N-terminal half of the chromodomain that reads H3K9me3, the core molecular function of HP1-beta.
How it diverges

This truncation deletes the N-terminal 43 residues of canonical CBX1, and domain annotation shows this segment overlaps the chromodomain itself (CATH chromo fold, SMART/Pfam/PROSITE chromo domain, PRINTS chromo domain subgroup) rather than flanking sequence — three independent domain calls diverge in this region. Localization signal (nuclear import, DeepLoc) is unaffected, and whole-protein biophysical character and SAE feature shifts are both below threshold, so this is not a general destabilization but a specific excision of part of the reader module.

Why it matters

CBX1/HP1-beta's defining activity is its chromodomain reading H3K9me3 to organize heterochromatin and recruit SUV39H1, PRC2, and DNA-damage machinery; removing roughly half of that domain would be expected to impair or abolish methyl-lysine reading, which is the molecular event this protein exists to perform. Because nuclear targeting is preserved, any truncated protein made from this isoform would likely still enter the nucleus but arrive without a functional H3K9me3-reading chromodomain, disconnecting it from the heterochromatin-binding and PRC2-recruitment activities described in the literature.

Domain lossTruncated functional region
LLM confidence medium

Structural confidence for this region is low (pTM <0.4, high PAE between removed and retained segments), so the fold-based P1/P2 signals could not corroborate the domain-annotation-based loss; the conclusion rests primarily on InterPro domain-boundary overlap rather than confirmed 3D disruption. Germline tolerance and disease-variant density in this region are unremarkable, which tempers confidence that this loss is clinically impactful even though it is conserved and translated.

Folding

Canonical (185 aa)
Download CIF
Isoform (143 aa)
Download CIF
Coloured by ESMFold2 pLDDT confidence (blue = high, orange/red = low). Differential region — residues 1–43 (lost from canonical) — 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 (1–43).

Evidence — click any tile for the differential-region detail

C Conservation Interesting
LLM reasoning
The N-terminal 44-aa segment that this truncation removes from canonical CBX1 is under strong, consistent purifying selection, arguing its loss is functionally consequential rather than tolerated variation. Amino-acid identity across primates and mammals is 100%, essentially matching the canonical protein's own baseline identity in each group (99.5% primate, 97.8% mammalian), so the region is conserved at least as strongly as the rest of the protein. Absolute phyloP over the unique region is 4.92 (well above the ~2 strong-constraint threshold) and is comparable to the shared region's 5.02, with an enrichment ratio near 1 (0.98) indicating no relative relaxation of constraint in the removed segment relative to retained sequence. Together these independent conservation signals converge on the same conclusion: this is deeply conserved coding sequence, not incidental N-terminal padding, so its removal by this truncation is likely to matter biologically.
Unique region 100.0% similar across primates
Unique region 100.0% similar across mammals
Unique region PhyloP: 4.92 — purifying selection
D Detection Interesting
LLM reasoning
This truncated start site has strong, convergent detection evidence: it is reproducibly used across 4 of 6 cell lines with highly significant p-values (e.g., HeLa p=6.4e-14, RPE1-Async p=9.0e-5), reaches a high initiation efficiency of 0.577 in HeLa (well above the 0.01 threshold, though lower in other lines at 0.015-0.044), and is independently confirmed at the protein level by a validated isoform-unique peptide via mass spec (best hyperscore 45.9, p=0.0002). The convergence of ribosome-profiling-based start-site usage across multiple cell lines with orthogonal peptide-level validation makes a strong case that this truncated isoform is a genuine, actively translated protein product rather than a low-confidence annotation artifact.
detected in 4/6 cell lines
Max Initiation Efficiency: 0.577
1/1 isoform-unique peptides validated
L Localization Not interesting
LLM reasoning
Removing the N-terminal 42-residue segment (which includes a lysine-rich stretch) does not change predicted subcellular targeting: both canonical and truncated isoform are predicted nuclear-localized with near-identical confidence (92.7% vs 94.4%), retain the same annotated nuclear localization signal, and remain soluble/non-membrane-associated. Neither a secretory signal peptide nor a mitochondrial transit peptide is predicted for either form, and the SignalP/TargetP probability deltas are negligible (<0.001). The loss of this N-terminal segment therefore shows no evidence of altering compartmental targeting in this dimension.
iso: Nucleus | canon: Nucleus
iso: noTP | canon: noTP
M Mutation Landscape Not interesting
LLM reasoning
No disease signal concentrates in the truncated N-terminal segment, and germline data independently shows that segment is tolerated, not constrained. ClinVar has zero pathogenic calls anywhere on this protein (confirmed empty by direct query), and the 12 any-significance ClinVar variants scatter thinly across canonical residues 5-176 (span=172, top position holds only 1 hit, essentially no clustering). COSMIC recurrence is likewise low (max 5 samples, at residue 2) and concentrated mostly in the shared region rather than the removed N-terminal 44 residues. The disease-density ratio (0.75, unique vs shared) and the gnomAD depletion ratio (1.55, i.e. more common variation in the unique region, consistent with tolerance) point the same direction: the removed segment shows no elevated disease burden and no germline constraint. Together this is a coherent negative result, not a conflict.
gnomAD variants 1.55× more in unique region — tolerant
Disease variants 1.34× less in unique region — depleted
P Predicted Structure Not interesting
LLM reasoning
The global pTM is very low for both isoform (0.348) and canonical (0.392) models, signaling an unreliable overall prediction, and this undermines every other signal in this category. The removed N-terminal 43 residues do show locally decent per-residue confidence (0.70-0.94, mean 0.809) but contain no qualifying secondary structure (only a 5-residue strand, below the 6-aa threshold) and are otherwise coil. Critically, the PAE between this removed region and the rest of the canonical protein averages 22.7 Å — the relative placement is essentially unresolved even though each part folds locally. The shared-region RMSD of 30 Å is not usable either, since the isoform's shared-region pLDDT collapses to 0.58 (vs 0.83 in canonical) and pTM is below the 0.50 gate, so that large RMSD reflects placement uncertainty in a low-confidence model rather than a genuine core refold. No integrated, load-bearing structural element is supported by this data.
pLDDT Differential Region: 0.809
Shared-Region RMSD: 30.12 Å
No helix or strand in diff region
S Structural Characteristics Interesting
LLM reasoning
This truncation removes the N-terminal 44 residues of CBX1 that overlap real InterPro-annotated domain calls, including the chromo domain signature, CATH-Gene3D chromo fold, chromo/chromo shadow domain (SMART, PROSITE, Pfam) and the PRINTS chromo domain subgroup entries — three distinct domain-level annotations diverge in this region, indicating the truncation likely excises or disrupts the chromodomain that mediates methyl-lysine histone binding, a clear functional consequence. Whole-protein biophysical shift did not fire: hydropathy, charge-fraction, and disorder deltas were all below cutoff (gravy delta -0.033, fraction-charged delta -0.026, disorder delta -0.004), so global biophysical character is largely preserved despite the domain loss. The sparse-autoencoder magnitude check also did not fire (top shared-feature shift 4.35 vs threshold 10.0), though several hundred features differ in presence, consistent with but not independently informative beyond the domain-level finding. The domain-loss signal alone is strong and specific enough to drive the verdict, since it directly implicates loss of a named, functionally characterized folded module rather than a generic sequence-composition change.
3 diverging domains
more hydrophobic (+0.22) · more charged (+0.10) · similar disorder
285 SAE features differ

Clinical variants

Differential region — lost N-terminus (canonical-only)

Pos (iso) AA change Consequence Source Clin. sig. AF (gnomAD) Impact AlphaMissense ESM-C ΔLLR Link
— K→K intronic gnomAD — 6.85e-07 — — 0.00 chr17-48076882-C-T
— K→E intronic gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -11.19 chr17-48076884-T-C
— L→L intronic gnomAD — 6.85e-07 — — 0.00 chr17-48076885-T-G
— L→L intronic gnomAD — 3.43e-06 — — 0.00 chr17-48076888-G-A
— L→R intronic gnomAD — 6.85e-07 damaging likely_pathogenic (0.84) -9.56 chr17-48076889-A-C
— Y→Y intronic gnomAD — 1.71e-05 — — 0.00 chr17-48076891-G-A
— E→D intronic gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -7.72 chr17-48076894-C-G
— K→R intronic gnomAD — 2.05e-06 — likely_benign (0.09) -5.18 chr17-48076901-T-C
— G→G intronic gnomAD — 3.42e-06 — — 0.00 chr17-48076903-G-A
— G→S intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.97 chr17-48076905-C-T
— K→K intronic gnomAD — 6.84e-07 — — 0.00 chr17-48076906-C-T
— V→V intronic gnomAD — 1.37e-06 — — 0.00 chr17-48076909-T-C
— V→L intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.76) -6.96 chr17-48076911-C-A
— V→V intronic gnomAD — 2.05e-06 — — 0.00 chr17-48076912-C-T
— V→A intronic gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -7.43 chr17-48076913-A-G
— R→Q intronic gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -9.25 chr17-48076916-C-T
— R→R intronic gnomAD — 6.84e-07 — — 0.00 chr17-48076917-G-T
— R→H intronic gnomAD — 2.74e-06 damaging likely_pathogenic (0.79) -7.03 chr17-48076919-C-T
— R→C intronic gnomAD — 1.23e-05 damaging likely_pathogenic (0.87) -7.12 chr17-48076920-G-A
— D→H intronic gnomAD — 1.37e-06 damaging likely_pathogenic (0.94) -7.89 chr17-48076923-C-G
— D→N intronic gnomAD — 1.85e-05 damaging likely_pathogenic (0.56) -4.01 chr17-48076923-C-T
— L→L intronic gnomAD — 6.84e-06 — — 0.00 chr17-48076924-G-A
— K→N intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -9.37 chr17-48076930-T-A
— V→V intronic gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-A
— V→V intronic gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-G
— V→V intronic gnomAD — 2.74e-06 — — 0.00 chr17-48076939-C-T
— E→E intronic gnomAD — 2.05e-06 — — 0.00 chr17-48076945-T-C
— E→E intronic gnomAD — 1.37e-06 — — 0.00 chr17-48076951-T-C
— E→G intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.77) -9.56 chr17-48076952-T-C
— E→Q intronic gnomAD — 1.37e-06 damaging likely_pathogenic (0.61) -9.81 chr17-48076956-C-G
— E→Q intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.62) -9.69 chr17-48076959-C-G
— E→K intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.83) -11.12 chr17-48076962-C-T
— L→L intronic gnomAD — 2.05e-06 — — 0.00 chr17-48076963-T-C
— V→V intronic gnomAD — 1.37e-06 — — 0.00 chr17-48076966-C-T
— V→L intronic gnomAD — 2.05e-06 damaging likely_benign (0.30) -7.78 chr17-48076968-C-A
— V→M intronic gnomAD — 2.74e-06 damaging likely_benign (0.24) -8.68 chr17-48076968-C-T
— V→V intronic gnomAD — 1.37e-06 — — 0.00 chr17-48076975-C-T
— V→G intronic gnomAD — 6.85e-07 damaging likely_benign (0.14) -8.75 chr17-48076976-A-C
— V→M intronic gnomAD — 7.53e-06 damaging likely_benign (0.13) -8.37 chr17-48076977-C-T
— K→N intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -9.00 chr17-48076978-T-A
— — intronic gnomAD — 1.37e-06 — — — chr17-48076978-TTTC-T
— K→I intronic gnomAD — 6.84e-07 damaging ambiguous (0.56) -11.69 chr17-48076979-T-A
— K→R intronic gnomAD — 9.58e-06 damaging likely_benign (0.12) -8.94 chr17-48076979-T-C
— K→* intronic gnomAD — 6.84e-07 damaging — — chr17-48076980-T-A
— K→E intronic gnomAD — 6.84e-07 damaging ambiguous (0.42) -9.69 chr17-48076980-T-C
— K→N intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.84) -9.87 chr17-48076981-C-A
— K→R intronic gnomAD — 6.84e-07 damaging likely_benign (0.12) -9.06 chr17-48076982-T-C
— K→N intronic gnomAD — 6.84e-07 damaging likely_pathogenic (0.73) -9.94 chr17-48076984-C-G
— — intronic gnomAD — 6.84e-07 — — — chr17-48076984-CTTG-C
— K→Q intronic gnomAD — 1.37e-06 damaging likely_benign (0.24) -10.25 chr17-48076986-T-G
— N→K intronic gnomAD — 1.85e-05 damaging likely_pathogenic (0.68) -8.87 chr17-48076987-G-C
— Q→Q intronic gnomAD — 6.84e-07 — — 0.00 chr17-48076990-T-C
— K→K intronic gnomAD — 2.74e-06 — — 0.00 chr17-48076993-T-C
— G→G intronic gnomAD — 6.85e-07 — — 0.00 chr17-48076999-C-A
— G→V intronic gnomAD — 6.85e-07 damaging likely_pathogenic (0.88) -9.25 chr17-48077000-C-A
— G→W intronic gnomAD — 6.85e-07 damaging likely_pathogenic (0.97) -12.31 chr17-48077001-C-A
— M→I intronic gnomAD — 1.37e-06 damaging — -10.94 chr17-48077002-C-G
— M→I intronic gnomAD — 6.85e-07 damaging — -10.94 chr17-48077002-C-T
— M→T intronic gnomAD — 6.85e-07 damaging — -11.50 chr17-48077003-A-G
— M→L intronic gnomAD — 6.85e-07 damaging — -11.19 chr17-48077004-T-G
— N→K intronic ClinVar Uncertain significance — damaging likely_pathogenic (0.68) -8.87 ClinVar:3827926
— E→V intronic ClinVar — — damaging likely_pathogenic (1.00) -11.31 ClinVar:4423332
— L→F intronic COSMIC — — — ambiguous (0.35) -6.53 COSV56681814
— E→K intronic COSMIC — — damaging likely_pathogenic (1.00) -10.19 COSV56682856
— G→S intronic COSMIC — — damaging likely_pathogenic (0.96) -7.97 COSV99847936
— R→R intronic COSMIC — — — — 0.00 COSV56682056
— R→* intronic COSMIC — — damaging — — COSV56681749
— L→I intronic COSMIC — — damaging likely_benign (0.28) -9.56 COSV56682110
— V→V intronic COSMIC — — — — 0.00 COSV99848141
— E→Q intronic COSMIC — — damaging likely_pathogenic (0.95) -11.25 COSV99848313
— E→K intronic COSMIC — — damaging likely_pathogenic (0.83) -9.56 COSV56681509
— V→L intronic COSMIC — — damaging likely_benign (0.20) -8.06 COSV56682280
— Q→K intronic COSMIC — — damaging ambiguous (0.37) -10.00 COSV56682149
— — intronic COSMIC — — damaging — — COSV56681712
— — intronic COSMIC — — damaging — — COSV56681499
— M→V intronic COSMIC — — damaging — -11.44 COSV56682591

76 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
1 G→G synonymous_variant gnomAD — 4.39e-05 — — 0.00 chr17-48076873-T-C
2 F→F synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076870-G-A
2 F→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV56682209
5 E→K missense_variant gnomAD — 7.10e-07 damaging likely_pathogenic (0.84) -9.50 chr17-48076177-C-T
5 E→Q missense_variant ClinVar — — damaging likely_pathogenic (0.60) -11.12 ClinVar:4423331
5 E→Q missense_variant COSMIC — — damaging likely_pathogenic (0.60) -11.12 COSV56681530
6 D→H missense_variant gnomAD — 7.06e-07 damaging likely_pathogenic (0.97) -12.12 chr17-48076174-C-G
7 N→D missense_variant gnomAD — 1.41e-06 damaging likely_pathogenic (0.97) -10.37 chr17-48076171-T-C
7 N→S missense_variant COSMIC — — damaging likely_pathogenic (0.59) -9.00 COSV56681968
10 E→D missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.56 COSV99848274
12 E→D missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.69 COSV99848151
14 N→N synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076148-G-A
15 L→L synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076147-G-A
18 P→P synonymous_variant gnomAD — 1.51e-05 — — 0.00 chr17-48076136-G-A
18 P→P synonymous_variant gnomAD — 6.88e-07 — — 0.00 chr17-48076136-G-C
18 P→P synonymous_variant COSMIC — — — — 0.00 COSV99847948
19 D→N missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.31 COSV99847954
20 L→L synonymous_variant gnomAD — 1.23e-05 — — 0.00 chr17-48076130-G-A
22 A→A synonymous_variant gnomAD — 5.48e-06 — — 0.00 chr17-48076124-A-G
22 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076124-A-T
22 A→G missense_variant gnomAD — 1.37e-06 damaging ambiguous (0.38) -9.94 chr17-48076125-G-C
25 L→L synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076115-C-T
25 L→L synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076117-G-A
25 L→L synonymous_variant COSMIC — — — — 0.00 COSV105045650
26 Q→* stop_gained COSMIC — — LoF — — COSV99848158
27 S→L missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.27) -9.37 chr17-48076110-G-A
27 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.27) -9.37 ClinVar:4648788
28 Q→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.33) -7.47 chr17-48076107-T-C
28 Q→* stop_gained COSMIC — — LoF — — COSV99848270
29 K→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.12) -6.44 chr17-48076104-T-C
29 K→Q missense_variant ClinVar Uncertain significance — damaging likely_benign (0.33) -8.75 ClinVar:4531663
30 T→A missense_variant gnomAD — 6.85e-07 — likely_benign (0.06) -6.06 chr17-48076102-T-C
32 H→P missense_variant gnomAD — 4.79e-06 — likely_benign (0.11) -7.21 chr17-48076095-T-G
34 T→R missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.23) -7.90 chr17-48076089-G-C
35 D→G missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.27 chr17-48076086-T-C
35 D→N missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.15 chr17-48076087-C-T
35 D→G missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.27 ClinVar:4220041
35 D→N missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.15 ClinVar:4220044
36 K→K synonymous_variant gnomAD — 4.04e-05 — — 0.00 chr17-48076082-T-C
36 K→I missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.43) -10.75 chr17-48076083-T-A
36 K→I missense_variant ClinVar Uncertain significance — damaging ambiguous (0.43) -10.75 ClinVar:4220042
37 S→S synonymous_variant gnomAD — 4.79e-06 — — 0.00 chr17-48076079-T-G
38 E→K missense_variant COSMIC — — damaging likely_benign (0.26) -8.68 COSV99848247
39 G→R missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -8.76 chr17-48076075-C-G
39 G→R missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.76 COSV56682528
42 R→H missense_variant gnomAD — 7.53e-06 damaging likely_pathogenic (0.89) -9.31 chr17-48076065-C-T
42 R→C missense_variant gnomAD — 6.16e-06 damaging likely_pathogenic (0.96) -9.31 chr17-48076066-G-A
42 R→H missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.89) -9.31 ClinVar:2290145
42 R→H missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.31 COSV56682901
42 R→C missense_variant COSMIC — — damaging likely_pathogenic (0.96) -9.31 COSV56682920
43 K→R missense_variant gnomAD — 8.90e-06 damaging likely_benign (0.11) -7.87 chr17-48076062-T-C
44 A→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.08) -6.34 chr17-48076060-C-T
44 A→T missense_variant ClinVar Uncertain significance — — likely_benign (0.08) -6.34 ClinVar:4220043
45 D→G missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.15) -8.36 chr17-48076056-T-C
46 S→A missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.06) -9.87 chr17-48076054-A-C
46 S→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.05) -7.31 chr17-48076054-A-T
50 D→V missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.13) -9.56 chr17-48076041-T-A
50 D→V missense_variant ClinVar Uncertain significance — damaging likely_benign (0.13) -9.56 ClinVar:2307098
50 D→N missense_variant COSMIC — — damaging likely_benign (0.11) -7.93 COSV56682563
51 K→K synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076037-C-T
51 K→R missense_variant gnomAD — 2.05e-06 — likely_benign (0.09) -4.90 chr17-48076038-T-C
51 K→E missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.18) -11.05 chr17-48076039-T-C
51 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682520
51 K→N missense_variant COSMIC — — damaging likely_benign (0.29) -9.30 COSV99848170
52 G→G synonymous_variant gnomAD — 2.06e-06 — — 0.00 chr17-48076034-T-C
52 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48076035-CCCTT-C
52 G→R missense_variant gnomAD — 2.74e-06 damaging ambiguous (0.54) -7.55 chr17-48076036-C-T
53 E→E synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076031-C-T
53 E→Q missense_variant COSMIC — — damaging likely_benign (0.23) -8.62 COSV99848203
54 E→D missense_variant gnomAD — 6.86e-07 — likely_benign (0.05) -5.84 chr17-48076028-C-G
55 S→S synonymous_variant gnomAD — 4.81e-06 — — 0.00 chr17-48076025-G-A
55 S→G missense_variant gnomAD — 6.86e-07 — likely_benign (0.06) -5.94 chr17-48076027-T-C
55 S→S synonymous_variant COSMIC — — — — 0.00 COSV99848275
57 P→P synonymous_variant gnomAD — 2.07e-06 — — 0.00 chr17-48076019-T-C
57 P→L missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -6.30 chr17-48076020-G-A
59 K→N missense_variant gnomAD — 6.90e-07 damaging likely_pathogenic (0.93) -10.37 chr17-48076013-C-A
59 K→K synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076013-C-T
60 K→N missense_variant gnomAD — 6.91e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48076010-C-G
60 K→R missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -5.37 chr17-48076011-T-C
60 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV56681336
60 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV99848297
61 — inframe_deletion gnomAD — 2.77e-06 — — — chr17-48076007-TTTC-T
61 K→R missense_variant gnomAD — 6.92e-07 — likely_benign (0.09) -6.75 chr17-48076008-T-C
62 E→G missense_variant gnomAD — 6.92e-07 damaging likely_benign (0.33) -8.81 chr17-48076005-T-C
63 E→V missense_variant gnomAD — 1.39e-06 damaging likely_benign (0.30) -8.24 chr17-48076002-T-A
63 E→Q missense_variant gnomAD — 6.94e-07 damaging ambiguous (0.43) -8.99 chr17-48076003-C-G
64 S→S synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075098-T-A
64 S→L missense_variant gnomAD — 6.85e-07 — likely_benign (0.08) -6.09 chr17-48075099-G-A
65 E→A missense_variant gnomAD — 6.85e-07 damaging ambiguous (0.50) -9.43 chr17-48075096-T-G
67 P→S missense_variant gnomAD — 6.84e-07 — ambiguous (0.53) -5.76 chr17-48075091-G-A
67 P→Q missense_variant COSMIC — — damaging likely_pathogenic (0.61) -7.20 COSV106082017
67 P→S missense_variant COSMIC — — — ambiguous (0.53) -5.76 COSV56682997
68 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -8.69 chr17-48075087-C-T
68 R→* stop_gained gnomAD — 2.05e-06 LoF — — chr17-48075088-G-A
68 R→* stop_gained COSMIC — — LoF — — COSV56682269
70 F→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.44 chr17-48075081-A-G
71 A→A synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075077-A-C
71 A→A synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075077-A-G
72 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -8.12 chr17-48075075-C-T
72 R→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48075076-G-A
72 R→R synonymous_variant COSMIC — — — — 0.00 COSV107309107
72 R→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV99847942
72 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.99) -8.12 COSV56683114
72 R→* stop_gained COSMIC — — LoF — — COSV104387334
73 G→D missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.62 COSV105045685
75 E→K missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.87) -7.54 chr17-48075067-C-T
75 E→E synonymous_variant COSMIC — — — — 0.00 COSV56681442
76 P→P synonymous_variant gnomAD — 1.97e-04 — — 0.00 chr17-48075062-C-T
76 P→L missense_variant gnomAD — 7.52e-06 damaging likely_pathogenic (1.00) -10.81 chr17-48075063-G-A
76 P→P synonymous_variant COSMIC — — — — 0.00 COSV99848187
76 P→Q missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56682499
76 P→S missense_variant COSMIC — — damaging likely_pathogenic (1.00) -9.69 COSV99848079
77 E→D missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -9.06 chr17-48075059-C-A
77 E→E synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075059-C-T
77 E→D missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.92) -9.06 ClinVar:4648787
77 E→K missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56681862
78 R→R synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075056-C-T
78 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.98) -7.87 COSV56682101
78 R→L missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.12 COSV99848174
79 I→V missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.69 chr17-48075055-T-C
81 G→A missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.44 COSV56682437
83 T→T synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48075041-T-C
85 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075035-G-A
86 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681832
88 E→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -10.00 chr17-48075028-C-G
89 L→L synonymous_variant gnomAD — 9.59e-06 — — 0.00 chr17-48075023-G-A
90 M→L missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48075022-T-A
90 M→V missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.99) -11.50 chr17-48075022-T-C
90 — inframe_deletion COSMIC — — — — — COSV56681204
91 F→F synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075017-G-A
92 L→P missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -13.06 chr17-48075015-A-G
92 L→L synonymous_variant COSMIC — — — — 0.00 COSV99848148
92 L→L synonymous_variant COSMIC — — — — 0.00 COSV56681918
93 M→I missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (0.97) -8.12 chr17-48075011-C-A
93 M→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.81 chr17-48075012-A-G
94 K→K synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48075008-T-C
94 K→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.87 chr17-48075009-T-G
96 K→R missense_variant gnomAD — 8.28e-06 — likely_benign (0.14) -6.94 chr17-48071577-T-C
97 N→K missense_variant COSMIC — — damaging likely_pathogenic (0.89) -8.94 COSV99848229
98 S→F missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.37 COSV56681364
101 A→A synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071561-A-G
102 D→D synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071558-G-A
104 V→L missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.25 chr17-48071554-C-G
106 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071546-G-A
106 A→D missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -12.00 chr17-48071547-G-T
106 A→V missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.62 COSV99848117
108 E→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071542-C-A
108 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.94 COSV56681808
110 N→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.91) -12.44 chr17-48071535-T-C
111 V→F missense_variant gnomAD — 2.74e-06 damaging likely_pathogenic (0.57) -8.73 chr17-48071533-C-A
111 V→V synonymous_variant COSMIC — — — — 0.00 COSV56681933
112 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682664
113 C→C synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071525-G-A
113 C→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -5.97 chr17-48071526-C-G
114 P→L missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.62 chr17-48071523-G-A
115 Q→Q synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071519-C-T
115 Q→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48071521-G-A
116 V→F missense_variant gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -12.05 chr17-48071518-C-A
118 I→I synonymous_variant COSMIC — — — — 0.00 COSV56681722
118 I→T missense_variant COSMIC — — damaging likely_pathogenic (1.00) -11.06 COSV56682067
119 S→S synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48071507-G-T
120 F→F synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071504-G-A
121 Y→Y synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071501-A-G
121 Y→C missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -11.94 chr17-48071502-T-C
124 R→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -11.06 COSV56682552
126 T→T synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071486-C-T
126 T→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -13.94 COSV56681836
128 H→H synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071480-A-G
129 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071477-G-A
129 S→F missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.97) -11.12 chr17-48071478-G-A
129 S→A missense_variant gnomAD — 6.84e-07 damaging likely_benign (0.27) -9.06 chr17-48071479-A-C
129 S→P missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.98) -11.81 chr17-48071479-A-G
129 S→T missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.44) -10.19 chr17-48071479-A-T
130 Y→Y synonymous_variant gnomAD — 2.94e-05 — — 0.00 chr17-48071474-G-A
130 Y→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071474-G-T
131 P→S missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.58) -8.75 chr17-48071473-G-A
131 P→S missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.75 COSV108798400
132 S→S synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071468-C-T
132 S→L missense_variant gnomAD — 2.05e-06 damaging likely_benign (0.21) -8.42 chr17-48071469-G-A
132 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.21) -8.42 ClinVar:3138046
132 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681272
132 S→* stop_gained COSMIC — — LoF — — COSV99848014
133 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.75) -12.00 COSV104555665
134 D→E missense_variant gnomAD — 4.80e-06 — likely_benign (0.09) -5.24 chr17-48071462-A-C
134 D→D synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071462-A-G
134 D→Y missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.71) -11.56 chr17-48071464-C-A
134 D→N missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.31) -10.18 chr17-48071464-C-T
134 D→E missense_variant ClinVar Uncertain significance — — likely_benign (0.09) -5.24 ClinVar:2517719
136 — inframe_deletion gnomAD — 2.06e-06 — — — chr17-48071456-GTCA-G
136 D→N missense_variant COSMIC — — damaging likely_benign (0.19) -8.62 COSV99848218
137 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.72) -9.62 COSV99848111
137 — frameshift_variant COSMIC — — LoF — — COSV56682928
138 K→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071452-T-A
139 D→V missense_variant gnomAD — 6.86e-07 damaging ambiguous (0.45) -9.47 chr17-48071448-T-A
139 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-C-CT
139 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-CTTTT-C
139 D→H missense_variant COSMIC — — damaging likely_pathogenic (0.73) -10.72 COSV56682228
139 D→Y missense_variant COSMIC — — damaging likely_pathogenic (0.65) -9.97 COSV56681987
140 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071445-TC-T
140 D→Y missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.68) -10.43 chr17-48071446-C-A
140 D→N missense_variant gnomAD — 6.86e-07 — likely_benign (0.27) -7.43 chr17-48071446-C-T
140 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071446-CA-C
142 N→K missense_variant gnomAD — 6.87e-07 damaging likely_pathogenic (0.68) -7.21 chr17-48071438-G-C
142 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48071439-TTCTTG-T
142 N→K missense_variant COSMIC — — damaging likely_pathogenic (0.68) -7.21 COSV56682095

205 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