Is ACTC1 p.Pro245Ser (c.733C>T) pathogenic?

ACTC1 p.Pro245Ser (c.733C>T) is classified Uncertain significance in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 8.47e-05%, nfe); Associated with hypertrophic cardiomyopathy 11.

What condition is associated with ACTC1 p.Pro245Ser (c.733C>T)?

ACTC1 p.Pro245Ser (c.733C>T) is associated with hypertrophic cardiomyopathy 11, atrial septal defect 5, dilated cardiomyopathy 1R (ClinVar).

How common is ACTC1 p.Pro245Ser (c.733C>T) in the general population?

ACTC1 p.Pro245Ser (c.733C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTC1 p.Pro245Ser (c.733C>T)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

ACTC1 p.Pro245Ser

c.733C>T · rs1891718375 · VCV2935885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 11

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 2,113 bp · p 8.3e-37 · regional, not allelic
Overall
CADD	28.4	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) · 1/1,180,056 alleles

Overall 6.2e-05% 1/1,614,114 alleles · very rare exomes 0/1,461,888 · genomes 1/152,226 · joint denominator

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.Pro245Ser
Coding: c.733C>T
MANE Select: NM_005159
dbSNP: rs1891718375
Type: single nucleotide variant
Location: chr15:34792165 (GRCh38)

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

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-pro245ser (accessed [today's date]).

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