Is ERBB3 p.His217Pro (c.650A>C) pathogenic?

ERBB3 p.His217Pro (c.650A>C) is classified Uncertain significance in ERBB3 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.7882); Absent from gnomAD v4.1; Associated with lethal congenital contracture syndrome 2.

What condition is associated with ERBB3 p.His217Pro (c.650A>C)?

ERBB3 p.His217Pro (c.650A>C) is associated with lethal congenital contracture syndrome 2 (ClinVar).

How common is ERBB3 p.His217Pro (c.650A>C) in the general population?

ERBB3 p.His217Pro (c.650A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERBB3 p.His217Pro (c.650A>C)?

AlphaMissense predicts likely pathogenic (score 0.7882) — an in-silico prediction, not a clinical call.

ERBB3 p.His217Pro

c.650A>C · rs2136793945 · VCV2585366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7882 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lethal congenital contracture syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7882	likely pathogenic
REVEL	0.263	benign-leaning
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.2	GERP 0.79, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 19 kb · p 5.7e-12 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERBB3
Protein: p.His217Pro
Coding: c.650A>C
MANE Select: NM_001982
dbSNP: rs2136793945
Type: single nucleotide variant
Location: chr12:56087831 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB

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

Disease context

lethal congenital contracture syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB3 p.Lys747Asn Uncertain significance ★★ ⚠ same condition
ERBB3 p.Pro1142Leu Uncertain significance ★★ ⚠ same condition
ERBB3 c.234+8A>T Benign ★★ same condition
ERBB3 c.2616+16G>C Benign/Likely benign ★★ same condition
ERBB3 c.3129+9A>C Benign ★★ same condition
ERBB3 p.Arg1116= Benign ★★ same condition
ERBB3 c.1184-9A>G Likely pathogenic ★ same condition
ERBB3 c.3202-2A>G Likely pathogenic ★ same condition

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-his217pro (accessed [today's date]).

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