Is ACTRT1 p.Pro244Leu (c.731C>T) pathogenic?

ACTRT1 p.Pro244Leu (c.731C>T) is classified Uncertain significance in ACTRT1 (ClinVar, Single submitter, 3 submitters; last evaluated 2025-05-28). AlphaMissense: likely benign (0.2525); Very rare (popmax 0.00816%, nfe).

How common is ACTRT1 p.Pro244Leu (c.731C>T) in the general population?

ACTRT1 p.Pro244Leu (c.731C>T) is very rare (popmax 0.00816%, nfe) (gnomAD).

What do computational predictors say about ACTRT1 p.Pro244Leu (c.731C>T)?

AlphaMissense predicts likely benign (score 0.2525) — an in-silico prediction, not a clinical call.

ACTRT1 p.Pro244Leu

c.731C>T · rs141055838 · VCV1328366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00816%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2525	likely benign
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,127 bp · p 0.013 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.00816% European (non-Finnish) · 73/894,913 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0061%

Overall 0.00621% 75/1,208,447 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00816%	12,259
Remaining individualsnot grpmax-eligible	0.0021%	47,570
South Asian	0.00176%	56,662

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.Pro244Leu
Coding: c.731C>T
MANE Select: NM_138289
dbSNP: rs141055838
Type: single nucleotide variant
Location: chrX:128051476 (GRCh38)
Structure: AlphaFold pLDDT 92.94
Residue 244: a UniProt-annotated variant site (found in a patient with bazex syndrome; uncertain significance)

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

Similar variants

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
ACTRT1 p.Arg231Leu 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-pro244leu (accessed [today's date]).

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