Is ACTA2 c.129+8A>C pathogenic?

ACTA2 c.129+8A>C is classified Likely benign in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 c.129+8A>C?

ACTA2 c.129+8A>C is associated with aortic aneurysm, familial thoracic 6 (ClinVar).

How common is ACTA2 c.129+8A>C in the general population?

ACTA2 c.129+8A>C is absent from gnomAD v4.1 (gnomAD).

ACTA2 c.129+8A>C

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

rs1845999194 · VCV1536661

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.093	GERP -2.2
Non-coding constraint	Z 2.78	1 kb window · o/e 0.80 · regional · uncalibrated
Overall
CADD	9.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTA2
Coding: c.129+8A>C
MANE Select: NM_001613
dbSNP: rs1845999194
Type: single nucleotide variant
Location: chr10:88948794 (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

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

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-c-129-plus-8a-c (accessed [today's date]).

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