Is ACTC1 p.His175fs (c.523dup) pathogenic?

ACTC1 p.His175fs (c.523dup) is classified Uncertain significance in ACTC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-25). Very rare (popmax 0.00178%, nfe); Associated with atrial septal defect 5.

What condition is associated with ACTC1 p.His175fs (c.523dup)?

ACTC1 p.His175fs (c.523dup) is associated with atrial septal defect 5, cardiomyopathy, hypertrophic cardiomyopathy 11 (ClinVar).

How common is ACTC1 p.His175fs (c.523dup) in the general population?

ACTC1 p.His175fs (c.523dup) is very rare (popmax 0.00178%, nfe) (gnomAD).

ACTC1 p.His175fs

c.523dup · rs730880389 · VCV180754

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Conditions

atrial septal defect 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 4 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,022 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0015% 22/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,191
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.His175fs
Coding: c.523dup
MANE Select: NM_005159
dbSNP: rs730880389
Type: Duplication
Location: chr15:34792500 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 175: an α-helix

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

Disease context

atrial septal defect 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy hypertrophic cardiomyopathy 11 dilated cardiomyopathy 1R

Similar variants

ACTC1 p.His175= Likely benign ★★ same residue
ACTC1 p.His175Arg Uncertain significance ★★ ⚠ same residue
ACTC1 p.Asn227fs Likely pathogenic ★ same condition
ACTC1 c.130-11dup Conflicting classifications of pathogenicity ★ same condition
ACTC1 p.Asn117delinsCysSerGlnArgProArgTer Uncertain significance ★ same condition
ACTC1 p.Asp224fs Uncertain significance ★ same condition
ACTC1 p.Phe202fs Uncertain significance ★ same condition
ACTC1 p.Glu101Lys 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-his175fs (accessed [today's date]).

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