Is ACTA2 p.Arg39Leu (c.116G>T) pathogenic?

ACTA2 p.Arg39Leu (c.116G>T) is classified Likely pathogenic in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.9791); Absent from gnomAD v4.1; Associated with ACTA2-related disorder.

What condition is associated with ACTA2 p.Arg39Leu (c.116G>T)?

ACTA2 p.Arg39Leu (c.116G>T) is associated with ACTA2-related disorder (ClinVar).

How common is ACTA2 p.Arg39Leu (c.116G>T) in the general population?

ACTA2 p.Arg39Leu (c.116G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA2 p.Arg39Leu (c.116G>T)?

AlphaMissense predicts likely pathogenic (score 0.9791) — an in-silico prediction, not a clinical call.

ACTA2 p.Arg39Leu

c.116G>T · VCV4908652

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9791 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9791	likely pathogenic ✓ concordant with ClinVar
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -14.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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
Protein: p.Arg39Leu
Coding: c.116G>T
MANE Select: NM_001613
Type: single nucleotide variant
Location: chr10:88948815 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43
Residue 39: a UniProt-annotated variant site (in aat6)

Full ACTA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTA2-related disorder

Similar variants

ACTA2 p.Arg39Cys Pathogenic/Likely pathogenic ★★ same residue
ACTA2 p.Arg39His Pathogenic/Likely pathogenic ★★ same residue
ACTA2 p.Arg39Gly Pathogenic/Likely pathogenic ★★ same residue
ACTA2 p.Arg39Ser Likely pathogenic ★ same residue
ACTA2 p.Arg118Gln Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg149Cys Pathogenic ★★ same condition
ACTA2 p.Arg198Cys 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-arg39leu (accessed [today's date]).

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