Is ERBB2 p.Ser457= (c.1371A>G) pathogenic?

ERBB2 p.Ser457= (c.1371A>G) is classified Benign in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). Common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele.

ERBB2 p.Ser457=

Q: How common is ERBB2 p.Ser457= (c.1371A>G) in the general population?

ERBB2 p.Ser457= (c.1371A>G) is common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1371A>G · rs2230698 · VCV1168005

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -5.3
Overall
CADD	0.094	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13% African / African-American · 9,725/75,010 alleles

Filtering AF 12.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.7%

Overall 0.725% 11,676/1,609,958 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13%	8
Admixed American	1.49%	67
Remaining individualsnot grpmax-eligible	0.96%	104
Middle Eastern	0.346%	289
Finnishnot grpmax-eligible	0.0584%	1,712
South Asian	0.0549%	1,822
European (non-Finnish)	0.0293%	3,410
East Asian	0.0111%	8,977

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.Ser457=
Coding: c.1371A>G
MANE Select: NM_004448
dbSNP: rs2230698
Type: single nucleotide variant
Location: chr17:39715797 (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-ser457 (accessed [today's date]).

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