Is ACTC1 p.Ile252= (c.756T>C) pathogenic?

ACTC1 p.Ile252= (c.756T>C) is classified Likely benign in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). Very rare (popmax 0.004%, afr); Associated with dilated cardiomyopathy 1R.

What condition is associated with ACTC1 p.Ile252= (c.756T>C)?

ACTC1 p.Ile252= (c.756T>C) is associated with dilated cardiomyopathy 1R, cardiomyopathy, hypertrophic cardiomyopathy 11 (ClinVar).

How common is ACTC1 p.Ile252= (c.756T>C) in the general population?

ACTC1 p.Ile252= (c.756T>C) is very rare (popmax 0.004%, afr) (gnomAD).

How is Left ventricular noncompaction inherited?

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

ACTC1 p.Ile252=

c.756T>C · rs371940910 · VCV1332130

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

dilated cardiomyopathy 1R

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -4.7
Overall
CADD	7.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,936 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,110 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.Ile252=
Coding: c.756T>C
MANE Select: NM_005159
dbSNP: rs371940910
Type: single nucleotide variant
Location: chr15:34792142 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 252: a β-strand

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

Disease context

dilated cardiomyopathy 1R — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy hypertrophic cardiomyopathy 11 atrial septal defect 5

For Left ventricular noncompaction (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages

Similar variants

ACTC1 p.Ile252Met Uncertain significance ★★ ⚠ same residue
ACTC1 p.Ile252Thr Uncertain significance ★★ ⚠ same residue
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

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-ile252 (accessed [today's date]).

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