Is ERBB4 p.Ala655Val (c.1964C>T) pathogenic?

ERBB4 p.Ala655Val (c.1964C>T) is classified Uncertain significance in ERBB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.4239); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERBB4 p.Ala655Val (c.1964C>T)?

ERBB4 p.Ala655Val (c.1964C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERBB4 p.Ala655Val (c.1964C>T) in the general population?

ERBB4 p.Ala655Val (c.1964C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ERBB4 p.Ala655Val (c.1964C>T)?

AlphaMissense predicts ambiguous (score 0.4239) — an in-silico prediction, not a clinical call.

ERBB4 p.Ala655Val

c.1964C>T · VCV4019159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4239	ambiguous
REVEL	0.448	indeterminate
SaProt	LLR -7.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.87 · regional, not allelic
Overall
CADD	27.9	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 0.000763% European (non-Finnish) · 9/1,179,604 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,744 alleles · very rare exomes 9/1,461,244 · genomes 0/151,500 · joint denominator

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: ERBB4
Protein: p.Ala655Val
Coding: c.1964C>T
MANE Select: NM_005235
Type: single nucleotide variant
Location: chr2:211630577 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB
Residue 655: an α-helix

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.Ala655= Likely benign ★ same residue
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

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-ala655val (accessed [today's date]).

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