Is ERBB4 p.Ala978Pro (c.2932G>C) pathogenic?

ERBB4 p.Ala978Pro (c.2932G>C) is classified Uncertain significance in ERBB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ERBB4 p.Ala978Pro (c.2932G>C)?

ERBB4 p.Ala978Pro (c.2932G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ERBB4 p.Ala978Pro (c.2932G>C) in the general population?

ERBB4 p.Ala978Pro (c.2932G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERBB4 p.Ala978Pro (c.2932G>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

ERBB4 p.Ala978Pro

c.2932G>C · rs2125406938 · VCV2331384

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 6% in ERBB4
REVEL	0.648	pathogenic-leaning
SaProt	LLR -17.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 210 kb · p 3.5e-09 · regional, not allelic
Overall
CADD	29.9	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

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: ERBB4
Protein: p.Ala978Pro
Coding: c.2932G>C
MANE Select: NM_005235
dbSNP: rs2125406938
Type: single nucleotide variant
Location: chr2:211422039 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB
Residue 978: the protein kinase domain

Full ERBB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB4 p.Arg393Gln Uncertain significance ★★ ⚠ same condition
ERBB4 p.Gln598Lys Uncertain significance ★★ same condition
ERBB4 p.Glu1138Gly Uncertain significance ★★ ⚠ same condition
ERBB4 p.Glu696Ala Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile337Val Uncertain significance ★★ ⚠ same condition
ERBB4 p.Lys291Arg Uncertain significance ★★ ⚠ same condition
ERBB4 p.Lys681Arg Uncertain significance ★★ ⚠ same condition
ERBB4 p.Lys873Thr Uncertain significance ★★ ⚠ 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/erbb4-p-ala978pro (accessed [today's date]).

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