Is ACTA2 p.Ile291Val (c.871A>G) pathogenic?

ACTA2 p.Ile291Val (c.871A>G) is classified Uncertain significance in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). AlphaMissense: ambiguous (0.488); Very rare (popmax 0.0011%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with ACTA2 p.Ile291Val (c.871A>G)?

ACTA2 p.Ile291Val (c.871A>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is ACTA2 p.Ile291Val (c.871A>G) in the general population?

ACTA2 p.Ile291Val (c.871A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACTA2 p.Ile291Val (c.871A>G)?

AlphaMissense predicts ambiguous (score 0.488) — an in-silico prediction, not a clinical call.

ACTA2 p.Ile291Val

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.871A>G · rs1231881251 · VCV3071963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.488	ambiguous
REVEL	0.578	indeterminate
SaProt	LLR -10.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	25.3	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 0.0011% South Asian · 1/91,078 alleles

Overall 0.000124% 2/1,614,034 alleles · very rare exomes 2/1,461,782 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	8.47e-05%	1,179,954

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.Ile291Val
Coding: c.871A>G
MANE Select: NM_001613
dbSNP: rs1231881251
Type: single nucleotide variant
Location: chr10:88938180 (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

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

ACTA2 p.Ile291Met Uncertain significance ★★ ⚠ same residue
ACTA2 p.Ile291Asn Uncertain significance ★ ⚠ same residue
ACTA2 p.Arg118Gln Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg149Cys Pathogenic ★★ same condition
ACTA2 p.Arg179Cys Pathogenic ★★ same condition
ACTA2 p.Arg179His Pathogenic ★★ same condition
ACTA2 p.Arg198Cys Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg198His Pathogenic/Likely 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-ile291val (accessed [today's date]).

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