Is ACTG2 p.Arg40His (c.119G>A) pathogenic?

ACTG2 p.Arg40His (c.119G>A) is classified Pathogenic/Likely pathogenic in ACTG2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.9851); Absent from gnomAD v4.1; Associated with megacystis-microcolon-intestinal hypoperistalsis syndrome 5.

What condition is associated with ACTG2 p.Arg40His (c.119G>A)?

ACTG2 p.Arg40His (c.119G>A) is associated with megacystis-microcolon-intestinal hypoperistalsis syndrome 5, constipation disorder, visceral neuropathy, familial, 3, autosomal dominant (ClinVar).

How common is ACTG2 p.Arg40His (c.119G>A) in the general population?

ACTG2 p.Arg40His (c.119G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTG2 p.Arg40His (c.119G>A)?

AlphaMissense predicts likely pathogenic (score 0.9851) — an in-silico prediction, not a clinical call.

ACTG2 p.Arg40His

c.119G>A · rs587777386 · VCV132802

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9851 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megacystis-microcolon-intestinal hypoperistalsis syndrome 5

Computational evidence

Protein change
AlphaMissense	0.9851	likely pathogenic ✓ concordant with ClinVar
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -13.79	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 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 18 kb · p 3.5e-30 · regional, not allelic
Overall
CADD	31.0	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: ACTG2
Protein: p.Arg40His
Coding: c.119G>A
MANE Select: NM_001615
dbSNP: rs587777386
Type: single nucleotide variant
Location: chr2:73901430 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 95.46 · 4 PDB
Residue 40: a UniProt-annotated variant site (in mmihs5; interferes with proper polymerization into thin filaments); a UniProt-annotated variant site (in vscm1 and mmihs5)

Full ACTG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megacystis-microcolon-intestinal hypoperistalsis syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: constipation disorder visceral neuropathy, familial, 3, autosomal dominant chronic intestinal pseudoobstruction visceral myopathy 1

Similar variants

ACTG2 p.Arg40Cys Pathogenic/Likely pathogenic ★★ same residue
ACTG2 p.Ala205Thr Pathogenic ★★ same condition
ACTG2 p.Arg148Cys Likely pathogenic ★★ same condition
ACTG2 p.Arg178Cys Pathogenic ★★ same condition
ACTG2 p.Arg178His Pathogenic ★★ same condition
ACTG2 p.Arg178Leu Pathogenic ★★ same condition
ACTG2 p.Arg211Gln Pathogenic/Likely pathogenic ★★ same condition
ACTG2 p.Arg257Cys 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/actg2-p-arg40his (accessed [today's date]).

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