Is ERBB2 p.Arg190Pro (c.569G>C) pathogenic?

ERBB2 p.Arg190Pro (c.569G>C) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: ambiguous (0.4566); Very rare (popmax 0.00449%, nfe).

How common is ERBB2 p.Arg190Pro (c.569G>C) in the general population?

ERBB2 p.Arg190Pro (c.569G>C) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Arg190Pro (c.569G>C)?

AlphaMissense predicts ambiguous (score 0.4566) — an in-silico prediction, not a clinical call.

ERBB2 p.Arg190Pro

c.569G>C · rs531563820 · VCV1448888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4566	ambiguous
REVEL	0.434	indeterminate
SaProt	LLR -9.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	18.68	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 0.00449% European (non-Finnish) · 53/1,179,986 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00347% 56/1,613,834 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,264
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00134%	74,828

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.Arg190Pro
Coding: c.569G>C
MANE Select: NM_004448
dbSNP: rs531563820
Type: single nucleotide variant
Location: chr17:39709447 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 190: a disulfide bond

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

Similar variants

ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same residue
ERBB2 p.Arg190Trp Uncertain significance ★ ⚠ same residue
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.Arg203His 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-arg190pro (accessed [today's date]).

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