Is ERBB2 p.Arg683Pro (c.2048G>C) pathogenic?

ERBB2 p.Arg683Pro (c.2048G>C) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9719); Very rare (popmax 0.00667%, amr).

How common is ERBB2 p.Arg683Pro (c.2048G>C) in the general population?

ERBB2 p.Arg683Pro (c.2048G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ERBB2 p.Arg683Pro (c.2048G>C)?

AlphaMissense predicts likely pathogenic (score 0.9719) — an in-silico prediction, not a clinical call.

ERBB2 p.Arg683Pro

c.2048G>C · rs765387989 · VCV2418763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9719	likely pathogenic
REVEL	0.606	indeterminate
SaProt	LLR -11.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,614,078 alleles · very rare

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.Arg683Pro
Coding: c.2048G>C
MANE Select: NM_004448
dbSNP: rs765387989
Type: single nucleotide variant
Location: chr17:39723420 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 683: the 'required for interaction with kpnb1 and eea1' region

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

Similar variants

ERBB2 p.Arg683Gln 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.Arg190Gln 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-arg683pro (accessed [today's date]).

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