Is ACTRT1 p.Ser18Leu (c.53C>T) pathogenic?

ACTRT1 p.Ser18Leu (c.53C>T) is classified Uncertain significance in ACTRT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-02). AlphaMissense: ambiguous (0.5182); Ultra-rare (popmax 0.0431%, nfe).

How common is ACTRT1 p.Ser18Leu (c.53C>T) in the general population?

ACTRT1 p.Ser18Leu (c.53C>T) is ultra-rare (popmax 0.0431%, nfe) (gnomAD).

What do computational predictors say about ACTRT1 p.Ser18Leu (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.5182) — an in-silico prediction, not a clinical call.

ACTRT1 p.Ser18Leu

c.53C>T · rs199614384 · VCV2343486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5182 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0431%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5182	ambiguous
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -14.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,127 bp · p 0.013 · regional, not allelic
Overall
CADD	23.3	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 0.0431% European (non-Finnish) · 385/893,613 alleles

Filtering AF 0.0395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0381%

Overall 0.0327% 395/1,206,919 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0431%	2,321
Remaining individualsnot grpmax-eligible	0.019%	5,269
African / African-American	0.00175%	57,125

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.Ser18Leu
Coding: c.53C>T
MANE Select: NM_138289
dbSNP: rs199614384
Type: single nucleotide variant
Location: chrX:128052154 (GRCh38)
Structure: AlphaFold pLDDT 92.94

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-ser18leu (accessed [today's date]).

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