Is ERBB2 p.Val1253Met (c.3757G>A) pathogenic?

ERBB2 p.Val1253Met (c.3757G>A) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely benign (0.0697); Rare (popmax 0.126%, eas).

How common is ERBB2 p.Val1253Met (c.3757G>A) in the general population?

ERBB2 p.Val1253Met (c.3757G>A) is rare (popmax 0.126%, eas) (gnomAD).

What do computational predictors say about ERBB2 p.Val1253Met (c.3757G>A)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

ERBB2 p.Val1253Met

c.3757G>A · rs36085723 · VCV1390013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.126%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0697	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -4.3, phastCons 0.82
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	10.17	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.126% East Asian · 56/44,584 alleles

Filtering AF 0.0993% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0898%

Overall 0.00473% 75/1,586,986 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.126%	796
Remaining individualsnot grpmax-eligible	0.00163%	61,456
European (non-Finnish)	0.00146%	68,668
African / African-American	0.00134%	74,560

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.Val1253Met
Coding: c.3757G>A
MANE Select: NM_004448
dbSNP: rs36085723
Type: single nucleotide variant
Location: chr17:39728033 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1253: the 'disordered' region

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

Similar variants

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
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg217Cys 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-val1253met (accessed [today's date]).

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