Is ERBB4 p.Ile892Val (c.2674A>G) pathogenic?

ERBB4 p.Ile892Val (c.2674A>G) is classified Uncertain significance in ERBB4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-16). AlphaMissense: likely pathogenic (0.6051); Ultra-rare (popmax 0.0334%, mid); Associated with ERBB4-related disorder.

What condition is associated with ERBB4 p.Ile892Val (c.2674A>G)?

ERBB4 p.Ile892Val (c.2674A>G) is associated with ERBB4-related disorder, amyotrophic lateral sclerosis type 19 (ClinVar).

How common is ERBB4 p.Ile892Val (c.2674A>G) in the general population?

ERBB4 p.Ile892Val (c.2674A>G) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about ERBB4 p.Ile892Val (c.2674A>G)?

AlphaMissense predicts likely pathogenic (score 0.6051) — an in-silico prediction, not a clinical call.

ERBB4 p.Ile892Val

c.2674A>G · rs149713914 · VCV1414531

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ERBB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.6051	likely pathogenic
REVEL	0.629	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 210 kb · p 3.5e-09 · regional, not allelic
Overall
CADD	25.7	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 0.0334% Middle Eastern · 2/5,994 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00731% 116/1,587,748 alleles · ultra-rare exomes 94/1,435,564 · genomes 22/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,997
Admixed American	0.0267%	3,746
Remaining individualsnot grpmax-eligible	0.0146%	6,839
European (non-Finnish)	0.00735%	13,610
African / African-American	0.00537%	18,633

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.Ile892Val
Coding: c.2674A>G
MANE Select: NM_005235
dbSNP: rs149713914
Type: single nucleotide variant
Location: chr2:211428453 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB
Residue 892: an α-helix; the protein kinase domain

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

Disease context

ERBB4-related disorder

Also linked: amyotrophic lateral sclerosis type 19

Similar variants

ERBB4 p.Ala158Thr Uncertain significance ★★ ⚠ same condition
ERBB4 p.Arg1175Ser Uncertain significance ★★ same condition
ERBB4 p.Gly1061Glu Uncertain significance ★★ ⚠ same condition
ERBB4 p.Gly1293Asp Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile666Thr Uncertain significance ★★ ⚠ same condition
ERBB4 p.Met343Leu Uncertain significance ★★ ⚠ same condition
ERBB4 p.Phe297Leu Uncertain significance ★★ ⚠ same condition
ERBB4 p.Pro170Ser 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-ile892val (accessed [today's date]).

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