Is ERBB2 p.Gly366Arg (c.1096G>C) pathogenic?

ERBB2 p.Gly366Arg (c.1096G>C) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.1701); Very rare (popmax 0.00322%, nfe).

How common is ERBB2 p.Gly366Arg (c.1096G>C) in the general population?

ERBB2 p.Gly366Arg (c.1096G>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Gly366Arg (c.1096G>C)?

AlphaMissense predicts likely benign (score 0.1701) — an in-silico prediction, not a clinical call.

ERBB2 p.Gly366Arg

c.1096G>C · rs767588058 · VCV1350118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1701	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -8.01	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 8.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	25.9	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 0.00322% European (non-Finnish) · 38/1,179,970 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0026% 42/1,613,854 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,052
Remaining individualsnot grpmax-eligible	0.0032%	31,236
Finnishnot grpmax-eligible	0.00156%	64,000
African / African-American	0.00133%	74,926

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.Gly366Arg
Coding: c.1096G>C
MANE Select: NM_004448
dbSNP: rs767588058
Type: single nucleotide variant
Location: chr17:39712396 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 366: a disulfide bond

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

Similar variants

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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-gly366arg (accessed [today's date]).

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