Is ACTRT1 p.Arg76Cys (c.226C>T) pathogenic?

ACTRT1 p.Arg76Cys (c.226C>T) is classified Uncertain significance in ACTRT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1665); Ultra-rare (popmax 0.0667%, sas).

How common is ACTRT1 p.Arg76Cys (c.226C>T) in the general population?

ACTRT1 p.Arg76Cys (c.226C>T) is ultra-rare (popmax 0.0667%, sas) (gnomAD).

What do computational predictors say about ACTRT1 p.Arg76Cys (c.226C>T)?

AlphaMissense predicts likely benign (score 0.1665) — an in-silico prediction, not a clinical call.

ACTRT1 p.Arg76Cys

c.226C>T · VCV3485249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1665 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1665	likely benign
REVEL	0.65	pathogenic-leaning
SaProt	LLR -9.78	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	phastCons 0.002
Regional constraint	o/e 1.15	unconstrained · MANE · 1,127 bp · p 0.013 · regional, not allelic
Overall
CADD	16.57	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

Grpmax group 0.0667% South Asian · 38/56,952 alleles

Filtering AF 0.0499% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0441%

Overall 0.00364% 40/1,098,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0667%	1,499
East Asian	0.00296%	33,732
Remaining individualsnot grpmax-eligible	0.0021%	47,643

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: ACTRT1
Protein: p.Arg76Cys
Coding: c.226C>T
MANE Select: NM_138289
Type: single nucleotide variant
Location: chrX:128051981 (GRCh38)
Structure: AlphaFold pLDDT 92.94

Full ACTRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTRT1 p.Arg76His Uncertain significance ★ ⚠ same residue
ACTRT1 p.Arg313Ser Benign ★★ same type
ACTRT1 p.Ser345Thr Benign ★★ ⚠ same type
ACTRT1 p.Ala141Val Uncertain significance ★ ⚠ same type
ACTRT1 p.Ala344Val Uncertain significance ★ ⚠ same type
ACTRT1 p.Ala361Glu Uncertain significance ★ ⚠ same type
ACTRT1 p.Arg194Leu Uncertain significance ★ ⚠ same type
ACTRT1 p.Arg194Trp 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/actrt1-p-arg76cys (accessed [today's date]).

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