Is ACTC1 p.Pro104Leu (c.311C>T) pathogenic?

ACTC1 p.Pro104Leu (c.311C>T) is classified Uncertain significance in ACTC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-07-12). AlphaMissense: likely pathogenic (0.9364); Very rare (popmax 8.47e-05%, nfe); Associated with dilated cardiomyopathy 1R.

What condition is associated with ACTC1 p.Pro104Leu (c.311C>T)?

ACTC1 p.Pro104Leu (c.311C>T) is associated with dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11, atrial septal defect 5 (ClinVar).

How common is ACTC1 p.Pro104Leu (c.311C>T) in the general population?

ACTC1 p.Pro104Leu (c.311C>T) is very rare (popmax 8.47e-05%, nfe) (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.Pro104Leu (c.311C>T)?

AlphaMissense predicts likely pathogenic (score 0.9364) — an in-silico prediction, not a clinical call.

ACTC1 p.Pro104Leu

c.311C>T · rs1405829098 · VCV636464

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1R

Computational evidence

Protein change
AlphaMissense	0.9364	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -16.98	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 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	33.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 0.000658% 1/152,090 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.Pro104Leu
Coding: c.311C>T
MANE Select: NM_005159
dbSNP: rs1405829098
Type: single nucleotide variant
Location: chr15:34793388 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB

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: 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.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-pro104leu (accessed [today's date]).

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