Is ERBB2 p.Ile655Val (c.1963A>G) pathogenic?

ERBB2 p.Ile655Val (c.1963A>G) is classified Benign in ERBB2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1335); Common (popmax 24.3%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERBB2 p.Ile655Val (c.1963A>G)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

ERBB2 p.Ile655Val

Q: How common is ERBB2 p.Ile655Val (c.1963A>G) in the general population?

ERBB2 p.Ile655Val (c.1963A>G) is common (popmax 24.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1963A>G · rs1136201 · VCV13873

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 24.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -5.81	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 8.1	GERP -1.9, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	19.24	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 24.3% European (non-Finnish) · 286,766/1,179,414 alleles

Filtering AF 24.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.2%

Overall 22.1% 355,922/1,611,762 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	29.8%	3
Amishnot grpmax-eligible	27.1%	4
European (non-Finnish)grpmax	24.3%	4
Remaining individualsnot grpmax-eligible	20%	5
Admixed American	16%	6
South Asian	15.7%	6
Ashkenazi Jewishnot grpmax-eligible	14.2%	7
Middle Eastern	13.1%	8
East Asian	12.6%	8
African / African-American	4%	25

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile655Val
Coding: c.1963A>G
MANE Select: NM_004448
dbSNP: rs1136201
Type: single nucleotide variant
Location: chr17:39723335 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 655: an α-helix; a UniProt-annotated variant site (in allele b2 and allele b3)

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

Similar variants

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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-ile655val (accessed [today's date]).

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