Is ERBB4 p.Ile658Phe (c.1972A>T) pathogenic?

ERBB4 p.Ile658Phe (c.1972A>T) is classified Conflicting classifications of pathogenicity in ERBB4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.669); Rare (popmax 0.239%, eas); Associated with amyotrophic lateral sclerosis type 19.

What condition is associated with ERBB4 p.Ile658Phe (c.1972A>T)?

ERBB4 p.Ile658Phe (c.1972A>T) is associated with amyotrophic lateral sclerosis type 19 (ClinVar).

How common is ERBB4 p.Ile658Phe (c.1972A>T) in the general population?

ERBB4 p.Ile658Phe (c.1972A>T) is rare (popmax 0.239%, eas) (gnomAD).

What do computational predictors say about ERBB4 p.Ile658Phe (c.1972A>T)?

AlphaMissense predicts likely pathogenic (score 0.669) — an in-silico prediction, not a clinical call.

ERBB4 p.Ile658Phe

c.1972A>T · rs190654033 · VCV1563977

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.669 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 19

Computational evidence

Protein change
AlphaMissense	0.669	likely pathogenic
REVEL	0.663	pathogenic-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.87 · regional, not allelic
Overall
CADD	25.9	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 0.239% East Asian · 107/44,808 alleles

Filtering AF 0.202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.188%

Overall 0.00924% 149/1,612,970 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.239%	419
South Asian	0.0395%	2,529
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00017%	589,897

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.Ile658Phe
Coding: c.1972A>T
MANE Select: NM_005235
dbSNP: rs190654033
Type: single nucleotide variant
Location: chr2:211630569 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB
Residue 658: an α-helix

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

Disease context

amyotrophic lateral sclerosis type 19 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB4 p.Ile658Thr Uncertain significance ★ ⚠ same residue
ERBB4 p.Ala158Thr Uncertain significance ★★ ⚠ same condition
ERBB4 p.Gly1293Asp Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile892Val 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
ERBB4 p.Thr731Met 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-ile658phe (accessed [today's date]).

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