Is ACTC1 p.Leu96Phe (c.286C>T) pathogenic?

ACTC1 p.Leu96Phe (c.286C>T) is classified Uncertain significance in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.992); Absent from gnomAD v4.1; Associated with hypertrophic cardiomyopathy 11.

What condition is associated with ACTC1 p.Leu96Phe (c.286C>T)?

ACTC1 p.Leu96Phe (c.286C>T) is associated with hypertrophic cardiomyopathy 11, atrial septal defect 5, dilated cardiomyopathy 1R (ClinVar).

How common is ACTC1 p.Leu96Phe (c.286C>T) in the general population?

ACTC1 p.Leu96Phe (c.286C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTC1 p.Leu96Phe (c.286C>T)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

ACTC1 p.Leu96Phe

c.286C>T · rs2140431992 · VCV2947441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 11

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -13.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 1,330 bp · p 2.8e-11 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTC1
Protein: p.Leu96Phe
Coding: c.286C>T
MANE Select: NM_005159
dbSNP: rs2140431992
Type: single nucleotide variant
Location: chr15:34793413 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 96: an α-helix

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

Disease context

hypertrophic cardiomyopathy 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atrial septal defect 5 dilated cardiomyopathy 1R

Similar variants

ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Ala297Ser Pathogenic ★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ same condition
ACTC1 p.Thr128Ile Likely pathogenic ★★ same condition
ACTC1 c.455-6G>A Uncertain significance ★★ same condition
ACTC1 c.808+1G>C Uncertain significance ★★ same condition
ACTC1 c.808+3G>A 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/actc1-p-leu96phe (accessed [today's date]).

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