Is ACTC1 p.Arg314His (c.941G>A) pathogenic?

ACTC1 p.Arg314His (c.941G>A) is classified Conflicting classifications of pathogenicity in ACTC1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-08-04). AlphaMissense: likely pathogenic (0.9942); Very rare (popmax 0.00167%, amr); Associated with dilated cardiomyopathy 1R.

What condition is associated with ACTC1 p.Arg314His (c.941G>A)?

ACTC1 p.Arg314His (c.941G>A) is associated with dilated cardiomyopathy 1R, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is ACTC1 p.Arg314His (c.941G>A) in the general population?

ACTC1 p.Arg314His (c.941G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Left ventricular noncompaction inherited?

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

What do computational predictors say about ACTC1 p.Arg314His (c.941G>A)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

ACTC1 p.Arg314His

c.941G>A · rs121912673 · VCV18323

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1R

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -14.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	32.0	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 0.00167% Admixed American · 1/59,980 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000993% 16/1,611,378 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,178
Admixed Americangrpmax	0.00167%	59,980
African / African-American	0.00134%	74,846
European (non-Finnish)	0.00102%	98,154

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg314His
Coding: c.941G>A
MANE Select: NM_005159
dbSNP: rs121912673
Type: single nucleotide variant
Location: chr15:34791163 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 314: a UniProt-annotated variant site (in cmd1r); an α-helix

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 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.Arg314= Likely benign ★★ same residue
ACTC1 p.Arg314Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Gly345Val Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Pro266Leu Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Ala297Ser Pathogenic ★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ 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-arg314his (accessed [today's date]).

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