Is ERBB4 p.Ile481Val (c.1441A>G) pathogenic?

ERBB4 p.Ile481Val (c.1441A>G) is classified Uncertain significance in ERBB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0609); Very rare (popmax 0.00223%, eas); Associated with amyotrophic lateral sclerosis type 10.

What condition is associated with ERBB4 p.Ile481Val (c.1441A>G)?

ERBB4 p.Ile481Val (c.1441A>G) is associated with amyotrophic lateral sclerosis type 10 (ClinVar).

How common is ERBB4 p.Ile481Val (c.1441A>G) in the general population?

ERBB4 p.Ile481Val (c.1441A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERBB4 p.Ile481Val (c.1441A>G)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

ERBB4 p.Ile481Val

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1441A>G · rs368860175 · VCV1424254

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 10

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.029	GERP -1.2, phastCons 0.002
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.87 · regional, not allelic
Overall
CADD	10.21	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 0.00223% East Asian · 1/44,868 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,938 alleles · very rare exomes 22/1,461,788 · genomes 3/152,150 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
South Asian	0.0022%	45,543
European (non-Finnish)	0.00178%	56,189
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Ile481Val
Coding: c.1441A>G
MANE Select: NM_005235
dbSNP: rs368860175
Type: single nucleotide variant
Location: chr2:211702015 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB
Residue 481: a β-strand

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

Disease context

amyotrophic lateral sclerosis type 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

ERBB4 p.Pro1165Arg Uncertain significance ★ ⚠ same condition
ERBB4 p.Ala158Thr Uncertain significance ★★ ⚠ same type
ERBB4 p.Arg1175Ser Uncertain significance ★★ same type
ERBB4 p.Arg393Gln Uncertain significance ★★ ⚠ same type
ERBB4 p.Arg47Ter Uncertain significance ★★ same type
ERBB4 p.Asn465Lys Uncertain significance ★★ ⚠ same type
ERBB4 p.Gln598Lys Uncertain significance ★★ same type
ERBB4 p.Glu1138Gly Uncertain significance ★★ ⚠ 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/erbb4-p-ile481val (accessed [today's date]).

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