Is ERBB2 p.Thr67Ala (c.199A>G) pathogenic?

ERBB2 p.Thr67Ala (c.199A>G) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-09). AlphaMissense: likely benign (0.0467); Very rare (popmax 0.00102%, nfe); Associated with glioma susceptibility 1.

What condition is associated with ERBB2 p.Thr67Ala (c.199A>G)?

ERBB2 p.Thr67Ala (c.199A>G) is associated with glioma susceptibility 1, gastric cancer, ovarian cancer (ClinVar).

How common is ERBB2 p.Thr67Ala (c.199A>G) in the general population?

ERBB2 p.Thr67Ala (c.199A>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Thr67Ala (c.199A>G)?

AlphaMissense predicts likely benign (score 0.0467) — an in-silico prediction, not a clinical call.

ERBB2 p.Thr67Ala

c.199A>G · rs778575008 · VCV1496387

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glioma susceptibility 1

Computational evidence

Protein change
AlphaMissense	0.0467	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -2.86	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 4	GERP -0.85, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,883 bp · p 0.54 · regional, not allelic
Overall
CADD	15.86	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 0.00102% European (non-Finnish) · 12/1,171,132 alleles

Filtering AF 0.000546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000432%

Overall 0.000752% 12/1,595,914 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.Thr67Ala
Coding: c.199A>G
MANE Select: NM_004448
dbSNP: rs778575008
Type: single nucleotide variant
Location: chr17:39707115 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB

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

Disease context

glioma susceptibility 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer ovarian cancer lung cancer visceral neuropathy, familial, 2, autosomal recessive

Similar variants

ERBB2 p.Thr67= 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-thr67ala (accessed [today's date]).

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