Is ACTRT2 p.Arg77His (c.230G>A) pathogenic?

ACTRT2 p.Arg77His (c.230G>A) is classified Uncertain significance in ACTRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.0828); Rare (popmax 0.25%, eas).

How common is ACTRT2 p.Arg77His (c.230G>A) in the general population?

ACTRT2 p.Arg77His (c.230G>A) is rare (popmax 0.25%, eas) (gnomAD).

What do computational predictors say about ACTRT2 p.Arg77His (c.230G>A)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

ACTRT2 p.Arg77His

c.230G>A · VCV4223269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.25%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -5.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,130 bp · p 0.66 · regional, not allelic
Overall
CADD	19.1	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 0.25% East Asian · 112/44,840 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.00787% 127/1,613,520 alleles · rare exomes 118/1,461,328 · genomes 9/152,192 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.25%	400
Remaining individualsnot grpmax-eligible	0.0048%	20,833
African / African-American	0.00267%	37,504
Admixed American	0.00167%	60,026
European (non-Finnish)	0.000763%	131,115

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: ACTRT2
Protein: p.Arg77His
Coding: c.230G>A
MANE Select: NM_080431
Type: single nucleotide variant
Location: chr1:3021916 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI 0.29 (gnomAD)
Structure: AlphaFold pLDDT 93.42

Full ACTRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTRT2 p.Ala135Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala178Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala224Asp Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala23Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala259Gly Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala259Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala323Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala361Thr Uncertain significance ★ ⚠ same type

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/actrt2-p-arg77his (accessed [today's date]).

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