Is ERBB2 p.Val697Met (c.2089G>A) pathogenic?

ERBB2 p.Val697Met (c.2089G>A) is classified Pathogenic in ERBB2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9014); Very rare (popmax 8.48e-05%, nfe); Associated with urinary bladder cancer.

What condition is associated with ERBB2 p.Val697Met (c.2089G>A)?

ERBB2 p.Val697Met (c.2089G>A) is associated with urinary bladder cancer (ClinVar).

How common is ERBB2 p.Val697Met (c.2089G>A) in the general population?

ERBB2 p.Val697Met (c.2089G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Val697Met (c.2089G>A)?

AlphaMissense predicts likely pathogenic (score 0.9014) — an in-silico prediction, not a clinical call.

ERBB2 p.Val697Met

c.2089G>A · rs2145811711 · VCV2582232

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

urinary bladder cancer

Computational evidence

Protein change
AlphaMissense	0.9014	likely pathogenic ✓ concordant with ClinVar
REVEL	0.378	indeterminate
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,325 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,424 alleles

Overall 6.85e-05% 1/1,460,308 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERBB2
Protein: p.Val697Met
Coding: c.2089G>A
MANE Select: NM_004448
dbSNP: rs2145811711
Type: single nucleotide variant
Location: chr17:39723541 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 697: an α-helix

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

urinary bladder cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB2 p.Gly309Arg Pathogenic same condition
ERBB2 p.Gly309Glu Pathogenic same condition
ERBB2 p.Ser653Phe Pathogenic ⚠ same condition
ERBB2 p.Val839Met Pathogenic ⚠ same condition
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same type
ERBB2 p.Ala644Thr Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erbb2-p-val697met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown