Is ACTC1 p.Glu366= (c.1098G>A) pathogenic?

ACTC1 p.Glu366= (c.1098G>A) is classified Likely benign in ACTC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-21). Ultra-rare (popmax 0.0165%, mid); Associated with atrial septal defect 5.

What condition is associated with ACTC1 p.Glu366= (c.1098G>A)?

ACTC1 p.Glu366= (c.1098G>A) is associated with atrial septal defect 5, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is ACTC1 p.Glu366= (c.1098G>A) in the general population?

ACTC1 p.Glu366= (c.1098G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ACTC1 p.Glu366=

c.1098G>A · rs758173419 · VCV377437

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

atrial septal defect 5

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 1.2	GERP -0.81, phastCons 1
Overall
CADD	7.947	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000805% 13/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
South Asian	0.00659%	15,181
Admixed American	0.00333%	30,001
African / African-American	0.00267%	37,459
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	8.47e-05%	1,180,027

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.Glu366=
Coding: c.1098G>A
MANE Select: NM_005159
dbSNP: rs758173419
Type: single nucleotide variant
Location: chr15:34790448 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 366: 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 hypertrophic cardiomyopathy 11 dilated cardiomyopathy 1R

Similar variants

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
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-glu366 (accessed [today's date]).

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