Is ERBB3 p.Arg490Cys (c.1468C>T) pathogenic?

ERBB3 p.Arg490Cys (c.1468C>T) is classified Uncertain significance in ERBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: ambiguous (0.45); Ultra-rare (popmax 0.0334%, amr).

How common is ERBB3 p.Arg490Cys (c.1468C>T) in the general population?

ERBB3 p.Arg490Cys (c.1468C>T) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about ERBB3 p.Arg490Cys (c.1468C>T)?

AlphaMissense predicts ambiguous (score 0.45) — an in-silico prediction, not a clinical call.

ERBB3 p.Arg490Cys

c.1468C>T · rs775042280 · VCV2243017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.45 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Computational evidence

Protein change
AlphaMissense	0.45	ambiguous
REVEL	0.354	indeterminate
SaProt	LLR -9.65	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 19 kb · p 5.7e-12 · regional, not allelic
Overall
CADD	23.2	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 0.0334% Admixed American · 20/59,932 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0018% 29/1,611,648 alleles · ultra-rare exomes 20/1,459,902 · genomes 9/151,746 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0334%	2,997
East Asian	0.00446%	22,430
South Asian	0.0011%	91,034
European (non-Finnish)	0.000509%	196,630

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: ERBB3
Protein: p.Arg490Cys
Coding: c.1468C>T
MANE Select: NM_001982
dbSNP: rs775042280
Type: single nucleotide variant
Location: chr12:56093538 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB
Residue 490: an α-helix

Full ERBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERBB3 p.Ile703Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Lys747Asn Uncertain significance ★★ ⚠ same type
ERBB3 p.Pro1142Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Pro238Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Trp373Arg Uncertain significance ★★ ⚠ same type
ERBB3 c.1109+202A>G Likely benign ★★ same type
ERBB3 c.1109+207G>A Benign ★★ same type
ERBB3 c.1860-128G>A Benign ★★ 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/erbb3-p-arg490cys (accessed [today's date]).

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