Is ERBB2 p.Ser22Asn (c.65G>A) pathogenic?

ERBB2 p.Ser22Asn (c.65G>A) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1004); Ultra-rare (popmax 0.0107%, amr).

How common is ERBB2 p.Ser22Asn (c.65G>A) in the general population?

ERBB2 p.Ser22Asn (c.65G>A) is ultra-rare (popmax 0.0107%, amr) (gnomAD).

What do computational predictors say about ERBB2 p.Ser22Asn (c.65G>A)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

ERBB2 p.Ser22Asn

c.65G>A · rs896376245 · VCV1353241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -8.59	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 5.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,883 bp · p 0.54 · regional, not allelic
Overall
CADD	20.4	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 0.0107% Admixed American · 4/37,436 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.000912% 13/1,424,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0107%	9,359
Remaining individualsnot grpmax-eligible	0.0055%	18,177
African / African-American	0.00148%	67,418
European (non-Finnish)	0.000458%	218,222

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.Ser22Asn
Coding: c.65G>A
MANE Select: NM_004448
dbSNP: rs896376245
Type: single nucleotide variant
Location: chr17:39700303 (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

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-ser22asn (accessed [today's date]).

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