Is ACTA2 p.Glu5Gln (c.13G>C) pathogenic?

ACTA2 p.Glu5Gln (c.13G>C) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-25). AlphaMissense: likely benign (0.2819); Very rare (popmax 0.00017%, nfe); Associated with multisystemic smooth muscle dysfunction syndrome.

How common is ACTA2 p.Glu5Gln (c.13G>C) in the general population?

ACTA2 p.Glu5Gln (c.13G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ACTA2 p.Glu5Gln (c.13G>C)?

AlphaMissense predicts likely benign (score 0.2819) — an in-silico prediction, not a clinical call.

ACTA2 p.Glu5Gln

Q: What condition is associated with ACTA2 p.Glu5Gln (c.13G>C)?

ACTA2 p.Glu5Gln (c.13G>C) is associated with multisystemic smooth muscle dysfunction syndrome, aortic aneurysm, familial thoracic 6 (ClinVar).

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

Typically Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

c.13G>C · rs886047453 · VCV301511

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multisystemic smooth muscle dysfunction syndrome

Computational evidence

Protein change
AlphaMissense	0.2819	likely benign
REVEL	0.681	pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	27.5	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 0.00017% European (non-Finnish) · 2/1,179,812 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,738 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: ACTA2
Protein: p.Glu5Gln
Coding: c.13G>C
MANE Select: NM_001613
dbSNP: rs886047453
Type: single nucleotide variant
Location: chr10:88948918 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43

Full ACTA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multisystemic smooth muscle dysfunction syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aortic aneurysm, familial thoracic 6

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Glu5= Likely benign ★★ same residue
ACTA2 p.Glu5Ala Uncertain significance ★★ ⚠ same residue
ACTA2 p.Glu5Lys Uncertain significance ★★ ⚠ same residue
FAS p.Trp5Cys Uncertain significance ★ ⚠ same residue
ACTA2 p.Arg118Gln Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg149Cys Pathogenic ★★ same condition
ACTA2 p.Arg149Leu Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg179Cys 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/acta2-p-glu5gln (accessed [today's date]).

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