Is ACTA2 p.Asn94Ser (c.281A>G) pathogenic?

ACTA2 p.Asn94Ser (c.281A>G) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-30). AlphaMissense: likely pathogenic (0.7588); Very rare (popmax 0.0011%, sas); Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Asn94Ser (c.281A>G)?

ACTA2 p.Asn94Ser (c.281A>G) is associated with aortic aneurysm, familial thoracic 6, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is ACTA2 p.Asn94Ser (c.281A>G) in the general population?

ACTA2 p.Asn94Ser (c.281A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACTA2 p.Asn94Ser (c.281A>G)?

AlphaMissense predicts likely pathogenic (score 0.7588) — an in-silico prediction, not a clinical call.

ACTA2 p.Asn94Ser

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.281A>G · rs756569259 · VCV1171477

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
AlphaMissense	0.7588	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -12.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.93	acceptor gain · deltas
Pangolin	Δ0.59	gain · loss 0.26 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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 · 1/91,066 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000806% 13/1,613,798 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,010
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	0.000848%	117,991

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn94Ser
Coding: c.281A>G
MANE Select: NM_001613
dbSNP: rs756569259
Type: single nucleotide variant
Location: chr10:88943885 (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: familial thoracic aortic aneurysm and aortic dissection

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Asn94Asp 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
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-asn94ser (accessed [today's date]).

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