Is ACTA2 p.Val203Ile (c.607G>A) pathogenic?

ACTA2 p.Val203Ile (c.607G>A) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-09-19). AlphaMissense: likely benign (0.2685); Ultra-rare (popmax 0.0165%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is ACTA2 p.Val203Ile (c.607G>A) in the general population?

ACTA2 p.Val203Ile (c.607G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACTA2 p.Val203Ile (c.607G>A)?

AlphaMissense predicts likely benign (score 0.2685) — an in-silico prediction, not a clinical call.

ACTA2 p.Val203Ile

Q: What condition is associated with ACTA2 p.Val203Ile (c.607G>A)?

ACTA2 p.Val203Ile (c.607G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 6 (ClinVar).

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.607G>A · rs397516684 · VCV44218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.2685	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00235% 38/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
East Asian	0.0134%	7,468
African / African-American	0.008%	12,504
South Asian	0.00769%	13,011
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00119%	84,278

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.Val203Ile
Coding: c.607G>A
MANE Select: NM_001613
dbSNP: rs397516684
Type: single nucleotide variant
Location: chr10:88941238 (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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

ACTA2 p.Val203Leu 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-val203ile (accessed [today's date]).

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