Is ERBB2 p.Met31Val (c.91A>G) pathogenic?

ERBB2 p.Met31Val (c.91A>G) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: ambiguous (0.4314); Very rare (popmax 0.00113%, sas).

How common is ERBB2 p.Met31Val (c.91A>G) in the general population?

ERBB2 p.Met31Val (c.91A>G) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about ERBB2 p.Met31Val (c.91A>G)?

AlphaMissense predicts ambiguous (score 0.4314) — an in-silico prediction, not a clinical call.

ERBB2 p.Met31Val

c.91A>G · rs998740859 · VCV2895522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4314 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Computational evidence

Protein change
AlphaMissense	0.4314	ambiguous
REVEL	0.552	indeterminate
SaProt	LLR -6.65	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.57, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,883 bp · p 0.54 · regional, not allelic
Overall
CADD	21.4	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 0.00113% South Asian · 1/88,106 alleles

Overall 0.000139% 2/1,441,612 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,106
European (non-Finnish)	8.55e-05%	1,169,918

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.Met31Val
Coding: c.91A>G
MANE Select: NM_004448
dbSNP: rs998740859
Type: single nucleotide variant
Location: chr17:39707007 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 31: a disulfide bond

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

Similar variants

ERBB2 p.Met31Leu Uncertain significance ★ ⚠ same residue
ERBB2 p.Met31Ile Likely benign ★ ⚠ same residue
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
ERBB2 p.Arg188His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg190Gln 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-met31val (accessed [today's date]).

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