Is ACTA2 p.Leu67= (c.201G>C) pathogenic?

ACTA2 p.Leu67= (c.201G>C) is classified Benign/Likely benign in ACTA2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0329%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with ACTA2 p.Leu67= (c.201G>C)?

ACTA2 p.Leu67= (c.201G>C) is associated with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome (ClinVar).

How common is ACTA2 p.Leu67= (c.201G>C) in the general population?

ACTA2 p.Leu67= (c.201G>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

ACTA2 p.Leu67=

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.201G>C · rs199773697 · VCV136278

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 1.1	GERP 1.1, phastCons 1
Overall
CADD	10.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00651% 105/1,613,862 alleles · ultra-rare exomes 93/1,461,740 · genomes 12/152,122 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
European (non-Finnish)	0.0078%	12,825
Remaining individualsnot grpmax-eligible	0.0064%	15,620
South Asian	0.00549%	18,216
Admixed American	0.00333%	29,996

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.Leu67=
Coding: c.201G>C
MANE Select: NM_001613
dbSNP: rs199773697
Type: single nucleotide variant
Location: chr10:88947315 (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

Also linked: aortic aneurysm, familial thoracic 6 multisystemic smooth muscle dysfunction syndrome

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

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
ACTA2 p.Arg198His Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg256Cys 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-leu67 (accessed [today's date]).

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