Is ACTA2 p.Asp26Glu (c.78C>A) pathogenic?

ACTA2 p.Asp26Glu (c.78C>A) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-11). AlphaMissense: likely pathogenic (0.963); Ultra-rare (popmax 0.0283%, amr); Associated with multisystemic smooth muscle dysfunction syndrome.

What condition is associated with ACTA2 p.Asp26Glu (c.78C>A)?

ACTA2 p.Asp26Glu (c.78C>A) is associated with multisystemic smooth muscle dysfunction syndrome, aortic aneurysm, familial thoracic 6, Moyamoya disease 5 (ClinVar).

How common is ACTA2 p.Asp26Glu (c.78C>A) in the general population?

ACTA2 p.Asp26Glu (c.78C>A) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about ACTA2 p.Asp26Glu (c.78C>A)?

AlphaMissense predicts likely pathogenic (score 0.963) — an in-silico prediction, not a clinical call.

ACTA2 p.Asp26Glu

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.78C>A · rs141538225 · VCV580143

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.963 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multisystemic smooth muscle dysfunction syndrome

Computational evidence

Protein change
AlphaMissense	0.963	likely pathogenic
REVEL	0.629	indeterminate
SaProt	LLR -11.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -4
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	5.179	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 0.0283% Admixed American · 17/59,986 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00112% 18/1,613,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Asp26Glu
Coding: c.78C>A
MANE Select: NM_001613
dbSNP: rs141538225
Type: single nucleotide variant
Location: chr10:88948853 (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

multisystemic smooth muscle dysfunction syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aortic aneurysm, familial thoracic 6 Moyamoya disease 5 familial thoracic aortic aneurysm and aortic dissection

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Asp26His Uncertain significance ★★ ⚠ same residue
ACTA2 p.Asp26= Benign/Likely benign ★★ same residue
ACTA2 p.Asp26Asn Uncertain significance ★ ⚠ same residue
ACTA2 p.Asp26Tyr 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

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-asp26glu (accessed [today's date]).

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