Is ERBB2 p.Thr245Met (c.734C>T) pathogenic?

ERBB2 p.Thr245Met (c.734C>T) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-12). AlphaMissense: likely benign (0.1357); Ultra-rare (popmax 0.0136%, nfe); Associated with ovarian cancer.

What condition is associated with ERBB2 p.Thr245Met (c.734C>T)?

ERBB2 p.Thr245Met (c.734C>T) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.Thr245Met (c.734C>T) in the general population?

ERBB2 p.Thr245Met (c.734C>T) is ultra-rare (popmax 0.0136%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Thr245Met (c.734C>T)?

AlphaMissense predicts likely benign (score 0.1357) — an in-silico prediction, not a clinical call.

ERBB2 p.Thr245Met

c.734C>T · rs376183465 · VCV134091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1357 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1357	likely benign
REVEL	0.507	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	26.0	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 0.0136% European (non-Finnish) · 160/1,179,734 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0109% 176/1,612,696 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0136%	7,373
South Asian	0.00878%	11,386
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0048%	20,817
East Asian	0.00223%	44,884
Finnishnot grpmax-eligible	0.00159%	63,022

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.Thr245Met
Coding: c.734C>T
MANE Select: NM_004448
dbSNP: rs376183465
Type: single nucleotide variant
Location: chr17:39710176 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 245: a β-strand; a disulfide bond

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

Disease context

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

Also linked: gastric cancer lung cancer glioma susceptibility 1 visceral neuropathy, familial, 2, autosomal recessive

Similar variants

ERBB2 p.Thr245= Likely benign ★ same residue
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg217Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg517Gln Uncertain significance ★★ ⚠ same condition

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-thr245met (accessed [today's date]).

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