Is ACTA2 p.Ala140= (c.420G>A) pathogenic?

ACTA2 p.Ala140= (c.420G>A) is classified Benign/Likely benign in ACTA2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0147%, afr); Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Ala140= (c.420G>A)?

ACTA2 p.Ala140= (c.420G>A) is associated with aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is ACTA2 p.Ala140= (c.420G>A) in the general population?

ACTA2 p.Ala140= (c.420G>A) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

ACTA2 p.Ala140=

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.420G>A · rs762567614 · VCV264091

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

aortic aneurysm, familial thoracic 6

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 -13	GERP -4
Overall
CADD	2.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,914 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00614% 99/1,613,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,810
East Asian	0.0134%	7,450
Remaining individualsnot grpmax-eligible	0.00801%	12,488
European (non-Finnish)	0.00593%	16,853
Admixed American	0.00501%	19,973
South Asian	0.0044%	22,705

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.Ala140=
Coding: c.420G>A
MANE Select: NM_001613
dbSNP: rs762567614
Type: single nucleotide variant
Location: chr10:88941819 (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

aortic aneurysm, familial thoracic 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multisystemic smooth muscle dysfunction syndrome familial thoracic aortic aneurysm and aortic dissection

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Ala140Pro Uncertain significance ★ ⚠ same residue
ACTA2 p.Ala140Val Conflicting classifications of pathogenicity ★ ⚠ 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
ACTA2 p.Arg179His Pathogenic ★★ same condition
ACTA2 p.Arg198Cys 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-ala140 (accessed [today's date]).

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