Is ERBB3 p.Pro372His (c.1115C>A) pathogenic?

ERBB3 p.Pro372His (c.1115C>A) is classified Uncertain significance in ERBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.3295); Ultra-rare (popmax 0.0165%, mid).

How common is ERBB3 p.Pro372His (c.1115C>A) in the general population?

ERBB3 p.Pro372His (c.1115C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ERBB3 p.Pro372His (c.1115C>A)?

AlphaMissense predicts likely benign (score 0.3295) — an in-silico prediction, not a clinical call.

ERBB3 p.Pro372His

c.1115C>A · VCV4019151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3295 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3295	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 0.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 19 kb · p 5.7e-12 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000868% 14/1,613,614 alleles · ultra-rare exomes 14/1,461,358 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00133%	75,008
European (non-Finnish)	0.000933%	107,234

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.Pro372His
Coding: c.1115C>A
MANE Select: NM_001982
Type: single nucleotide variant
Location: chr12:56092752 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB
Residue 372: a turn

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-pro372his (accessed [today's date]).

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