SwissIsoform v2

CBX1 · ENST00000225603.9

EXTENDED 189 aa (canonical 185 aa) · UniProt P83916 · CDLMPS

chr17:48077016:-:CTG:ENST00000225603.9

AI summary A 4-residue N-terminal add-on leaves nuclear targeting, domains, and biophysics essentially untouched despite a locally well-folded tip.
How it diverges

The only notable tier-2 signal is that the added MAGT segment folds locally with decent confidence (P1), but the large apparent shared-region RMSD and PAE data show this segment's placement relative to the HP1-beta body is unresolved rather than a genuine docked element, so it does not qualify as a confidently integrated structured extension. Localization (still nucleus, NLS retained), domain content (no InterPro domain gained/lost), and whole-protein biophysics (negligible GRAVY/charge/disorder shifts) are all unchanged from canonical.

Why it matters

CBX1/HP1-beta's core functions — H3K9me3 reading via its chromodomain, SUV39H1/PRC2 complex assembly, and CK2/Chk2-regulated chromatin mobilization — all depend on nuclear localization and an intact chromodomain/chromoshadow architecture, none of which this extension perturbs: the isoform remains predicted nuclear with its NLS intact and gains no new domain. The seemingly large core-fold RMSD is not trustworthy evidence of altered chromodomain folding given the low pTM and high inter-region PAE, so no functional consequence for heterochromatin reading or complex assembly can be inferred from it.

LLM confidence low

The 13.9 Å shared-region RMSD and the extension's local pLDDT are undermined by low global pTM (~0.4) and high diff-vs-body PAE (~29 Å), so neither a core refold nor a structured N-terminal extension can be confidently claimed; only D3 (mass spec) is negative among existence evidence, but detection and conservation are otherwise strong, arguing the ORF is real even though no functional mechanism change is well supported.

Folding

Canonical (185 aa)
Download CIF
Isoform (189 aa)
Download CIF
Coloured by ESMFold2 pLDDT confidence (blue = high, orange/red = low). Differential region — residues 1–4 (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 (1–4).

Evidence — click any tile for the differential-region detail

C Conservation Interesting
LLM reasoning
The 4-residue N-terminal extension (MAGT) added ahead of the canonical CBX1 start shows essentially perfect amino-acid identity across both primates (100%) and mammals (100%), matching or exceeding the canonical region's own baseline identity (99.5% and 97.8% respectively) in this gene, and the reading frame is intact in all queried species with a conserved start codon. Absolute phyloP over this unique region is 6.36, well above the strong-constraint threshold, and actually higher than the shared/canonical region's own phyloP (4.95), with an enrichment ratio of 1.28. Together this is a strong, consistent purifying-selection signal across all three independent conservation axes, arguing this extension is a genuine, evolutionarily maintained coding sequence rather than incidental UTR read-through.
Unique region 100.0% similar across primates
Unique region 100.0% similar across mammals
Unique region PhyloP: 6.36 — purifying selection
D Detection Interesting
LLM reasoning
This N-terminal-extension TIS shows strong ribosome-profiling support: it is reproducibly detected in 5 of 6 cell lines, with genome-wide-significant p-values in every positive line, and start-site usage reaches a max initiation efficiency of 0.709 (K562), far above the 0.01 threshold, with strong statistical support (fisher q=2.2e-29). This indicates the alternative start codon is genuinely and efficiently used at the ribosome level across multiple cellular contexts. The one gap is proteomic: none of the 4 isoform-unique tryptic peptides (6-8 aa, spanning the short MAGT extension) were validated by PepQuery2, which is unsurprising given the very short unique region limits peptide detectability by mass spec. Given the robust, multi-line, statistically strong translation initiation signal, the category reads as interesting despite the negative (but low-power) peptide validation.
detected in 5/6 cell lines
Max Initiation Efficiency: 0.709
0/4 isoform-unique peptides validated
L Localization Not interesting
LLM reasoning
The short 4-residue N-terminal extension (MAGT) added ahead of the canonical start does not alter predicted subcellular fate: both isoform and canonical are predicted nuclear with a retained nuclear localization signal and soluble (non-membrane) status, with near-identical top-class probabilities (0.922 vs 0.927). Sorting-signal predictions are also unchanged — no signal peptide (OTHER/OTHER) and no transit peptide (noTP/noTP) in either form, with negligible probability deltas. Together these indicate the extension does not introduce or remove any targeting signal and leaves the compartment prediction unchanged, arguing against a localization-based functional consequence for this isoform.
iso: Nucleus | canon: Nucleus
iso: noTP | canon: noTP
M Mutation Landscape Not interesting
LLM reasoning
No meaningful disease signal supports functional consequence for this N-terminal extension. This is an extension isoform, so the germline depletion ratio and ESM-C constraint score are structurally uninterpretable (the added MAGT region was never coding) and cannot be used as evidence either way. The one member that remains valid — disease-variant density — is quiet: zero ClinVar pathogenic/likely-pathogenic variants exist anywhere on the isoform (n_matched=0), and the 12 total disease-associated records are spread diffusely across residues 9-180 (isoform numbering) with no clustering (the busiest position, 81, carries only 2 hits). The unique region itself contains only intronic gnomAD/COSMIC variants at very low allele frequency, none clinically flagged, consistent with pre-start-codon sequence that was never under coding constraint. No variant sits at or disrupts the alternative start codon. Taken together, the data gives no positive signal that the added segment is disease-relevant or functionally consequential.
gnomAD variants 1.45× more in unique region — tolerant
Disease variants comparable in unique region — neutral
P Predicted Structure Not interesting
LLM reasoning
The 4-residue N-terminal extension (MAGT) shows no credible sign of being a real, integrated structural element. Its local pLDDT is moderate (0.82-0.84 at residues 1-2, decaying to ~0.75 by residue 8), but the PAE between the extension (residues 1-4) and the rest of the isoform (residues 5-189) averages 28.6 Å — near the top of the 0-32 Å scale — meaning its placement relative to the folded body is essentially unresolved despite locally plausible per-residue confidence. Its only Ca contacts are with residues 5-6, i.e. immediate sequence neighbors, not a distinct patch suggesting a docked interface. The reported 7-aa "strand" spanning residues 2-8 is therefore geometry drawn from a poorly placed segment, not integration evidence. Global pTM is low for both isoform (0.42) and canonical (0.39), and the reported shared-region RMSD of 13.9 Å is consistent with placement uncertainty rather than a genuine core reorganization, given this confidence gate. Overall this reads as a short, low-confidence extension with no functional structural signal.
pLDDT Differential Region: 0.822
Shared-Region RMSD: 13.94 Å
1 secondary structure identified in unique region
S Structural Characteristics Not interesting
LLM reasoning
None of the three structural-characteristics submodules show a meaningful signal for this 4-residue N-terminal extension (MAGT) on CBX1. No real InterPro domain overlaps the differential region (0 domains changed; the diff-region hits are only MobiDB-lite disorder and a COILS coiled-coil prediction, not curated domains). Whole-protein biophysical shift is negligible: gravy delta +0.04, fraction-charged delta -0.01, disorder delta -0.006, all far below any threshold for a distinct shift. The sparse-autoencoder magnitude check also falls well short of its threshold (top shared-feature |delta| 2.80 vs threshold 10.0), so despite 26 gained and 10 lost features (expected given the length difference), no strong activation shift accompanies the extension. Together this argues the added 4 residues do not perturb domain content, bulk biophysical character, or embedding-level representation in any detectable way, consistent with a short, inert N-terminal addition rather than a functionally consequential structural change.
No diverging domains
more hydrophobic (+1.93) · less charged (-0.46) · less disordered (-0.26)
36 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 — 6.85e-07 — N/A — chr17-48077016-G-A
0 L→V missense_variant gnomAD — 2.19e-05 — N/A — chr17-48077016-G-C
1 A→A synonymous_variant gnomAD — 3.70e-05 — N/A 0.00 chr17-48077011-C-T
1 A→V missense_variant gnomAD — 6.85e-07 — N/A -1.75 chr17-48077012-G-A
1 A→V missense_variant COSMIC — — — N/A -1.75 COSV56682161
2 G→G synonymous_variant gnomAD — 6.85e-07 — N/A 0.00 chr17-48077008-G-A
2 G→G synonymous_variant COSMIC — — — N/A 0.00 COSV56681939
3 T→T synonymous_variant gnomAD — 6.85e-07 — N/A 0.00 chr17-48077005-A-G

8 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
4 M→I missense_variant gnomAD — 1.37e-06 damaging — -10.94 chr17-48077002-C-G
4 M→I missense_variant gnomAD — 6.85e-07 damaging — -10.94 chr17-48077002-C-T
4 M→T missense_variant gnomAD — 6.85e-07 damaging — -11.50 chr17-48077003-A-G
4 M→L missense_variant gnomAD — 6.85e-07 damaging — -11.19 chr17-48077004-T-G
4 M→V missense_variant COSMIC — — damaging — -11.44 COSV56682591
5 G→G synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076999-C-A
5 G→V missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.88) -9.25 chr17-48077000-C-A
5 G→W missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.97) -12.31 chr17-48077001-C-A
6 — frameshift_variant COSMIC — — LoF — — COSV56681712
6 — frameshift_variant COSMIC — — LoF — — COSV56681499
7 K→K synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48076993-T-C
8 Q→Q synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076990-T-C
8 Q→K missense_variant COSMIC — — damaging ambiguous (0.37) -10.00 COSV56682149
9 N→K missense_variant gnomAD — 1.85e-05 damaging likely_pathogenic (0.68) -8.87 chr17-48076987-G-C
9 N→K missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.68) -8.87 ClinVar:3827926
10 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.73) -9.94 chr17-48076984-C-G
10 — inframe_deletion gnomAD — 6.84e-07 — — — chr17-48076984-CTTG-C
10 K→Q missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.24) -10.25 chr17-48076986-T-G
11 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.84) -9.87 chr17-48076981-C-A
11 K→R missense_variant gnomAD — 6.84e-07 damaging likely_benign (0.12) -9.06 chr17-48076982-T-C
12 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -9.00 chr17-48076978-T-A
12 — inframe_deletion gnomAD — 1.37e-06 — — — chr17-48076978-TTTC-T
12 K→I missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.56) -11.69 chr17-48076979-T-A
12 K→R missense_variant gnomAD — 9.58e-06 damaging likely_benign (0.12) -8.94 chr17-48076979-T-C
12 K→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48076980-T-A
12 K→E missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.42) -9.69 chr17-48076980-T-C
13 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076975-C-T
13 V→G missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.14) -8.75 chr17-48076976-A-C
13 V→M missense_variant gnomAD — 7.53e-06 damaging likely_benign (0.13) -8.37 chr17-48076977-C-T
13 V→L missense_variant COSMIC — — damaging likely_benign (0.20) -8.06 COSV56682280
16 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076966-C-T
16 V→L missense_variant gnomAD — 2.05e-06 damaging likely_benign (0.30) -7.78 chr17-48076968-C-A
16 V→M missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.24) -8.68 chr17-48076968-C-T
17 L→L synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076963-T-C
18 E→K missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.83) -11.12 chr17-48076962-C-T
19 E→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.62) -9.69 chr17-48076959-C-G
19 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.83) -9.56 COSV56681509
20 E→Q missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.61) -9.81 chr17-48076956-C-G
21 E→E synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076951-T-C
21 E→G missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.77) -9.56 chr17-48076952-T-C
22 E→Q missense_variant COSMIC — — damaging likely_pathogenic (0.95) -11.25 COSV99848313
23 E→E synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076945-T-C
25 V→V synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48076939-C-T
25 V→V synonymous_variant COSMIC — — — — 0.00 COSV99848141
26 V→V synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-A
26 V→V synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076936-C-G
27 E→V missense_variant ClinVar — — damaging likely_pathogenic (1.00) -11.31 ClinVar:4423332
28 K→N missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -9.37 chr17-48076930-T-A
30 L→L synonymous_variant gnomAD — 6.84e-06 — — 0.00 chr17-48076924-G-A
30 L→I missense_variant COSMIC — — damaging likely_benign (0.28) -9.56 COSV56682110
31 D→H missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.94) -7.89 chr17-48076923-C-G
31 D→N missense_variant gnomAD — 1.85e-05 damaging likely_pathogenic (0.56) -4.01 chr17-48076923-C-T
32 R→H missense_variant gnomAD — 2.74e-06 damaging likely_pathogenic (0.79) -7.03 chr17-48076919-C-T
32 R→C missense_variant gnomAD — 1.23e-05 damaging likely_pathogenic (0.87) -7.12 chr17-48076920-G-A
33 R→Q missense_variant gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -9.25 chr17-48076916-C-T
33 R→R synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076917-G-T
33 R→R synonymous_variant COSMIC — — — — 0.00 COSV56682056
33 R→* stop_gained COSMIC — — LoF — — COSV56681749
34 V→V synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48076912-C-T
34 V→A missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -7.43 chr17-48076913-A-G
35 V→V synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076909-T-C
35 V→L missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.76) -6.96 chr17-48076911-C-A
36 K→K synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48076906-C-T
37 G→G synonymous_variant gnomAD — 3.42e-06 — — 0.00 chr17-48076903-G-A
37 G→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.97 chr17-48076905-C-T
37 G→S missense_variant COSMIC — — damaging likely_pathogenic (0.96) -7.97 COSV99847936
38 K→R missense_variant gnomAD — 2.05e-06 — likely_benign (0.09) -5.18 chr17-48076901-T-C
40 E→D missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -7.72 chr17-48076894-C-G
40 E→K missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.19 COSV56682856
41 Y→Y synonymous_variant gnomAD — 1.71e-05 — — 0.00 chr17-48076891-G-A
42 L→L synonymous_variant gnomAD — 3.43e-06 — — 0.00 chr17-48076888-G-A
42 L→R missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.84) -9.56 chr17-48076889-A-C
42 L→F missense_variant COSMIC — — — ambiguous (0.35) -6.53 COSV56681814
43 L→L synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076885-T-G
44 K→K synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076882-C-T
44 K→E missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -11.19 chr17-48076884-T-C
47 G→G synonymous_variant gnomAD — 4.39e-05 — — 0.00 chr17-48076873-T-C
48 F→F synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076870-G-A
48 F→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV56682209
51 E→K missense_variant gnomAD — 7.10e-07 damaging likely_pathogenic (0.84) -9.50 chr17-48076177-C-T
51 E→Q missense_variant ClinVar — — damaging likely_pathogenic (0.60) -11.12 ClinVar:4423331
51 E→Q missense_variant COSMIC — — damaging likely_pathogenic (0.60) -11.12 COSV56681530
52 D→H missense_variant gnomAD — 7.06e-07 damaging likely_pathogenic (0.97) -12.12 chr17-48076174-C-G
53 N→D missense_variant gnomAD — 1.41e-06 damaging likely_pathogenic (0.97) -10.37 chr17-48076171-T-C
53 N→S missense_variant COSMIC — — damaging likely_pathogenic (0.59) -9.00 COSV56681968
56 E→D missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.56 COSV99848274
58 E→D missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.69 COSV99848151
60 N→N synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076148-G-A
61 L→L synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076147-G-A
64 P→P synonymous_variant gnomAD — 1.51e-05 — — 0.00 chr17-48076136-G-A
64 P→P synonymous_variant gnomAD — 6.88e-07 — — 0.00 chr17-48076136-G-C
64 P→P synonymous_variant COSMIC — — — — 0.00 COSV99847948
65 D→N missense_variant COSMIC — — damaging likely_pathogenic (0.96) -8.31 COSV99847954
66 L→L synonymous_variant gnomAD — 1.23e-05 — — 0.00 chr17-48076130-G-A
68 A→A synonymous_variant gnomAD — 5.48e-06 — — 0.00 chr17-48076124-A-G
68 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076124-A-T
68 A→G missense_variant gnomAD — 1.37e-06 damaging ambiguous (0.38) -9.94 chr17-48076125-G-C
71 L→L synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076115-C-T
71 L→L synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48076117-G-A
71 L→L synonymous_variant COSMIC — — — — 0.00 COSV105045650
72 Q→* stop_gained COSMIC — — LoF — — COSV99848158
73 S→L missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.27) -9.37 chr17-48076110-G-A
73 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.27) -9.37 ClinVar:4648788
74 Q→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.33) -7.47 chr17-48076107-T-C
74 Q→* stop_gained COSMIC — — LoF — — COSV99848270
75 K→R missense_variant gnomAD — 6.85e-07 — likely_benign (0.12) -6.44 chr17-48076104-T-C
75 K→Q missense_variant ClinVar Uncertain significance — damaging likely_benign (0.33) -8.75 ClinVar:4531663
76 T→A missense_variant gnomAD — 6.85e-07 — likely_benign (0.06) -6.06 chr17-48076102-T-C
78 H→P missense_variant gnomAD — 4.79e-06 — likely_benign (0.11) -7.21 chr17-48076095-T-G
80 T→R missense_variant gnomAD — 2.74e-06 damaging likely_benign (0.23) -7.90 chr17-48076089-G-C
81 D→G missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.27 chr17-48076086-T-C
81 D→N missense_variant gnomAD — 6.84e-07 — likely_benign (0.10) -6.15 chr17-48076087-C-T
81 D→G missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.27 ClinVar:4220041
81 D→N missense_variant ClinVar Uncertain significance — — likely_benign (0.10) -6.15 ClinVar:4220044
82 K→K synonymous_variant gnomAD — 4.04e-05 — — 0.00 chr17-48076082-T-C
82 K→I missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.43) -10.75 chr17-48076083-T-A
82 K→I missense_variant ClinVar Uncertain significance — damaging ambiguous (0.43) -10.75 ClinVar:4220042
83 S→S synonymous_variant gnomAD — 4.79e-06 — — 0.00 chr17-48076079-T-G
84 E→K missense_variant COSMIC — — damaging likely_benign (0.26) -8.68 COSV99848247
85 G→R missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.58) -8.76 chr17-48076075-C-G
85 G→R missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.76 COSV56682528
88 R→H missense_variant gnomAD — 7.53e-06 damaging likely_pathogenic (0.89) -9.31 chr17-48076065-C-T
88 R→C missense_variant gnomAD — 6.16e-06 damaging likely_pathogenic (0.96) -9.31 chr17-48076066-G-A
88 R→H missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.89) -9.31 ClinVar:2290145
88 R→H missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.31 COSV56682901
88 R→C missense_variant COSMIC — — damaging likely_pathogenic (0.96) -9.31 COSV56682920
89 K→R missense_variant gnomAD — 8.90e-06 damaging likely_benign (0.11) -7.87 chr17-48076062-T-C
90 A→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.08) -6.34 chr17-48076060-C-T
90 A→T missense_variant ClinVar Uncertain significance — — likely_benign (0.08) -6.34 ClinVar:4220043
91 D→G missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.15) -8.36 chr17-48076056-T-C
92 S→A missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.06) -9.87 chr17-48076054-A-C
92 S→T missense_variant gnomAD — 1.37e-06 — likely_benign (0.05) -7.31 chr17-48076054-A-T
96 D→V missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.13) -9.56 chr17-48076041-T-A
96 D→V missense_variant ClinVar Uncertain significance — damaging likely_benign (0.13) -9.56 ClinVar:2307098
96 D→N missense_variant COSMIC — — damaging likely_benign (0.11) -7.93 COSV56682563
97 K→K synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48076037-C-T
97 K→R missense_variant gnomAD — 2.05e-06 — likely_benign (0.09) -4.90 chr17-48076038-T-C
97 K→E missense_variant gnomAD — 6.85e-07 damaging likely_benign (0.18) -11.05 chr17-48076039-T-C
97 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682520
97 K→N missense_variant COSMIC — — damaging likely_benign (0.29) -9.30 COSV99848170
98 G→G synonymous_variant gnomAD — 2.06e-06 — — 0.00 chr17-48076034-T-C
98 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48076035-CCCTT-C
98 G→R missense_variant gnomAD — 2.74e-06 damaging ambiguous (0.54) -7.55 chr17-48076036-C-T
99 E→E synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48076031-C-T
99 E→Q missense_variant COSMIC — — damaging likely_benign (0.23) -8.62 COSV99848203
100 E→D missense_variant gnomAD — 6.86e-07 — likely_benign (0.05) -5.84 chr17-48076028-C-G
101 S→S synonymous_variant gnomAD — 4.81e-06 — — 0.00 chr17-48076025-G-A
101 S→G missense_variant gnomAD — 6.86e-07 — likely_benign (0.06) -5.94 chr17-48076027-T-C
101 S→S synonymous_variant COSMIC — — — — 0.00 COSV99848275
103 P→P synonymous_variant gnomAD — 2.07e-06 — — 0.00 chr17-48076019-T-C
103 P→L missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -6.30 chr17-48076020-G-A
105 K→N missense_variant gnomAD — 6.90e-07 damaging likely_pathogenic (0.93) -10.37 chr17-48076013-C-A
105 K→K synonymous_variant gnomAD — 1.38e-06 — — 0.00 chr17-48076013-C-T
106 K→N missense_variant gnomAD — 6.91e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48076010-C-G
106 K→R missense_variant gnomAD — 1.38e-06 — likely_benign (0.09) -5.37 chr17-48076011-T-C
106 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV56681336
106 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.91) -10.25 COSV99848297
107 — inframe_deletion gnomAD — 2.77e-06 — — — chr17-48076007-TTTC-T
107 K→R missense_variant gnomAD — 6.92e-07 — likely_benign (0.09) -6.75 chr17-48076008-T-C
108 E→G missense_variant gnomAD — 6.92e-07 damaging likely_benign (0.33) -8.81 chr17-48076005-T-C
109 E→V missense_variant gnomAD — 1.39e-06 damaging likely_benign (0.30) -8.24 chr17-48076002-T-A
109 E→Q missense_variant gnomAD — 6.94e-07 damaging ambiguous (0.43) -8.99 chr17-48076003-C-G
110 S→S synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075098-T-A
110 S→L missense_variant gnomAD — 6.85e-07 — likely_benign (0.08) -6.09 chr17-48075099-G-A
111 E→A missense_variant gnomAD — 6.85e-07 damaging ambiguous (0.50) -9.43 chr17-48075096-T-G
113 P→S missense_variant gnomAD — 6.84e-07 — ambiguous (0.53) -5.76 chr17-48075091-G-A
113 P→Q missense_variant COSMIC — — damaging likely_pathogenic (0.61) -7.20 COSV106082017
113 P→S missense_variant COSMIC — — — ambiguous (0.53) -5.76 COSV56682997
114 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -8.69 chr17-48075087-C-T
114 R→* stop_gained gnomAD — 2.05e-06 LoF — — chr17-48075088-G-A
114 R→* stop_gained COSMIC — — LoF — — COSV56682269
116 F→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.44 chr17-48075081-A-G
117 A→A synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075077-A-C
117 A→A synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075077-A-G
118 R→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.99) -8.12 chr17-48075075-C-T
118 R→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48075076-G-A
118 R→R synonymous_variant COSMIC — — — — 0.00 COSV107309107
118 R→L missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.37 COSV99847942
118 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.99) -8.12 COSV56683114
118 R→* stop_gained COSMIC — — LoF — — COSV104387334
119 G→D missense_variant COSMIC — — damaging likely_pathogenic (0.89) -9.62 COSV105045685
121 E→K missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.87) -7.54 chr17-48075067-C-T
121 E→E synonymous_variant COSMIC — — — — 0.00 COSV56681442
122 P→P synonymous_variant gnomAD — 1.97e-04 — — 0.00 chr17-48075062-C-T
122 P→L missense_variant gnomAD — 7.52e-06 damaging likely_pathogenic (1.00) -10.81 chr17-48075063-G-A
122 P→P synonymous_variant COSMIC — — — — 0.00 COSV99848187
122 P→Q missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56682499
122 P→S missense_variant COSMIC — — damaging likely_pathogenic (1.00) -9.69 COSV99848079
123 E→D missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.92) -9.06 chr17-48075059-C-A
123 E→E synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48075059-C-T
123 E→D missense_variant ClinVar Uncertain significance — damaging likely_pathogenic (0.92) -9.06 ClinVar:4648787
123 E→K missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.12 COSV56681862
124 R→R synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075056-C-T
124 R→Q missense_variant COSMIC — — damaging likely_pathogenic (0.98) -7.87 COSV56682101
124 R→L missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.12 COSV99848174
125 I→V missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.96) -7.69 chr17-48075055-T-C
127 G→A missense_variant COSMIC — — damaging likely_pathogenic (1.00) -12.44 COSV56682437
129 T→T synonymous_variant gnomAD — 2.74e-06 — — 0.00 chr17-48075041-T-C
131 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48075035-G-A
132 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681832
134 E→Q missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.92) -10.00 chr17-48075028-C-G
135 L→L synonymous_variant gnomAD — 9.59e-06 — — 0.00 chr17-48075023-G-A
136 M→L missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.91) -10.25 chr17-48075022-T-A
136 M→V missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.99) -11.50 chr17-48075022-T-C
136 — inframe_deletion COSMIC — — — — — COSV56681204
137 F→F synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48075017-G-A
138 L→P missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -13.06 chr17-48075015-A-G
138 L→L synonymous_variant COSMIC — — — — 0.00 COSV99848148
138 L→L synonymous_variant COSMIC — — — — 0.00 COSV56681918
139 M→I missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (0.97) -8.12 chr17-48075011-C-A
139 M→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.81 chr17-48075012-A-G
140 K→K synonymous_variant gnomAD — 6.86e-07 — — 0.00 chr17-48075008-T-C
140 K→T missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.87 chr17-48075009-T-G
142 K→R missense_variant gnomAD — 8.28e-06 — likely_benign (0.14) -6.94 chr17-48071577-T-C
143 N→K missense_variant COSMIC — — damaging likely_pathogenic (0.89) -8.94 COSV99848229
144 S→F missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.37 COSV56681364
147 A→A synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071561-A-G
148 D→D synonymous_variant gnomAD — 6.87e-07 — — 0.00 chr17-48071558-G-A
150 V→L missense_variant gnomAD — 6.86e-07 damaging likely_pathogenic (1.00) -11.25 chr17-48071554-C-G
152 A→A synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071546-G-A
152 A→D missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (1.00) -12.00 chr17-48071547-G-T
152 A→V missense_variant COSMIC — — damaging likely_pathogenic (1.00) -10.62 COSV99848117
154 E→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071542-C-A
154 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -10.94 COSV56681808
156 N→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.91) -12.44 chr17-48071535-T-C
157 V→F missense_variant gnomAD — 2.74e-06 damaging likely_pathogenic (0.57) -8.73 chr17-48071533-C-A
157 V→V synonymous_variant COSMIC — — — — 0.00 COSV56681933
158 K→K synonymous_variant COSMIC — — — — 0.00 COSV56682664
159 C→C synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071525-G-A
159 C→S missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -5.97 chr17-48071526-C-G
160 P→L missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -10.62 chr17-48071523-G-A
161 Q→Q synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071519-C-T
161 Q→* stop_gained gnomAD — 6.84e-07 LoF — — chr17-48071521-G-A
162 V→F missense_variant gnomAD — 2.05e-06 damaging likely_pathogenic (0.99) -12.05 chr17-48071518-C-A
164 I→I synonymous_variant COSMIC — — — — 0.00 COSV56681722
164 I→T missense_variant COSMIC — — damaging likely_pathogenic (1.00) -11.06 COSV56682067
165 S→S synonymous_variant gnomAD — 2.05e-06 — — 0.00 chr17-48071507-G-T
166 F→F synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071504-G-A
167 Y→Y synonymous_variant gnomAD — 1.37e-06 — — 0.00 chr17-48071501-A-G
167 Y→C missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (1.00) -11.94 chr17-48071502-T-C
170 R→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -11.06 COSV56682552
172 T→T synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071486-C-T
172 T→K missense_variant COSMIC — — damaging likely_pathogenic (0.99) -13.94 COSV56681836
174 H→H synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071480-A-G
175 S→S synonymous_variant gnomAD — 6.84e-07 — — 0.00 chr17-48071477-G-A
175 S→F missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.97) -11.12 chr17-48071478-G-A
175 S→A missense_variant gnomAD — 6.84e-07 damaging likely_benign (0.27) -9.06 chr17-48071479-A-C
175 S→P missense_variant gnomAD — 6.84e-07 damaging likely_pathogenic (0.98) -11.81 chr17-48071479-A-G
175 S→T missense_variant gnomAD — 6.84e-07 damaging ambiguous (0.44) -10.19 chr17-48071479-A-T
176 Y→Y synonymous_variant gnomAD — 2.94e-05 — — 0.00 chr17-48071474-G-A
176 Y→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071474-G-T
177 P→S missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.58) -8.75 chr17-48071473-G-A
177 P→S missense_variant COSMIC — — damaging likely_pathogenic (0.58) -8.75 COSV108798400
178 S→S synonymous_variant gnomAD — 4.11e-06 — — 0.00 chr17-48071468-C-T
178 S→L missense_variant gnomAD — 2.05e-06 damaging likely_benign (0.21) -8.42 chr17-48071469-G-A
178 S→L missense_variant ClinVar Uncertain significance — damaging likely_benign (0.21) -8.42 ClinVar:3138046
178 S→S synonymous_variant COSMIC — — — — 0.00 COSV56681272
178 S→* stop_gained COSMIC — — LoF — — COSV99848014
179 E→K missense_variant COSMIC — — damaging likely_pathogenic (0.75) -12.00 COSV104555665
180 D→E missense_variant gnomAD — 4.80e-06 — likely_benign (0.09) -5.24 chr17-48071462-A-C
180 D→D synonymous_variant gnomAD — 6.85e-07 — — 0.00 chr17-48071462-A-G
180 D→Y missense_variant gnomAD — 6.85e-07 damaging likely_pathogenic (0.71) -11.56 chr17-48071464-C-A
180 D→N missense_variant gnomAD — 1.37e-06 damaging likely_benign (0.31) -10.18 chr17-48071464-C-T
180 D→E missense_variant ClinVar Uncertain significance — — likely_benign (0.09) -5.24 ClinVar:2517719
182 — inframe_deletion gnomAD — 2.06e-06 — — — chr17-48071456-GTCA-G
182 D→N missense_variant COSMIC — — damaging likely_benign (0.19) -8.62 COSV99848218
183 K→N missense_variant COSMIC — — damaging likely_pathogenic (0.72) -9.62 COSV99848111
183 — frameshift_variant COSMIC — — LoF — — COSV56682928
184 K→* stop_gained gnomAD — 6.85e-07 LoF — — chr17-48071452-T-A
185 D→V missense_variant gnomAD — 6.86e-07 damaging ambiguous (0.45) -9.47 chr17-48071448-T-A
185 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-C-CT
185 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071449-CTTTT-C
185 D→H missense_variant COSMIC — — damaging likely_pathogenic (0.73) -10.72 COSV56682228
185 D→Y missense_variant COSMIC — — damaging likely_pathogenic (0.65) -9.97 COSV56681987
186 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071445-TC-T
186 D→Y missense_variant gnomAD — 1.37e-06 damaging likely_pathogenic (0.68) -10.43 chr17-48071446-C-A
186 D→N missense_variant gnomAD — 6.86e-07 — likely_benign (0.27) -7.43 chr17-48071446-C-T
186 — frameshift_variant gnomAD — 6.86e-07 LoF — — chr17-48071446-CA-C
188 N→K missense_variant gnomAD — 6.87e-07 damaging likely_pathogenic (0.68) -7.21 chr17-48071438-G-C
188 — frameshift_variant gnomAD — 1.37e-06 LoF — — chr17-48071439-TTCTTG-T
188 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