Is ACTC1 p.Ile284Phe (c.850A>T) pathogenic?

ACTC1 p.Ile284Phe (c.850A>T) is classified Likely pathogenic in ACTC1 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.9806); Very rare (popmax 8.48e-05%, nfe); Associated with hypertrophic cardiomyopathy.

What condition is associated with ACTC1 p.Ile284Phe (c.850A>T)?

ACTC1 p.Ile284Phe (c.850A>T) is associated with hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 11, atrial septal defect 5 (ClinVar).

How common is ACTC1 p.Ile284Phe (c.850A>T) in the general population?

ACTC1 p.Ile284Phe (c.850A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTC1 p.Ile284Phe (c.850A>T)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

ACTC1 p.Ile284Phe

c.850A>T · rs397517073 · VCV45191

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

ClinGen expert panel — Cardiomyopathy VCEP

Likely Pathogenic for hypertrophic cardiomyopathy. Applied ACMG criteria (verbatim):

PM2_Supporting PP1_Moderate PS4_Moderate PP3

Curation rationale (ClinGen, verbatim)

NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe) - This variant has been identified in individuals with HCM as well as other cardiomyopathies (deciphergenomics.org, OMGL data, PMID 27532257) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criteria has been applied. This variant segregated with disease in 3 affected relatives with HCM in 3 families and 3 affected relatives with DCM/LVNC in one family (UK Laboratories; PP1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). Therefore, this variant is classified as Likely Pathogenic for HCM in an autosomal dominant manner based on PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic ✓ concordant with ClinVar
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	27.6	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 8.48e-05% European (non-Finnish) · 1/1,179,930 alleles

Overall 6.84e-05% 1/1,461,772 alleles · very rare

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: ACTC1
Protein: p.Ile284Phe
Coding: c.850A>T
dbSNP: rs397517073
Type: single nucleotide variant
Location: chr15:34791254 (GRCh38)

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy 11 atrial septal defect 5 dilated cardiomyopathy 1R

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/actc1-p-ile284phe (accessed [today's date]).

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