Is ACTRT1 p.Ser345Thr (c.1033T>A) pathogenic?

ACTRT1 p.Ser345Thr (c.1033T>A) is classified Benign in ACTRT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-03-30). AlphaMissense: ambiguous (0.397); Low-frequency (popmax 3.5%, afr).

How common is ACTRT1 p.Ser345Thr (c.1033T>A) in the general population?

ACTRT1 p.Ser345Thr (c.1033T>A) is low-frequency (popmax 3.5%, afr) (gnomAD).

What do computational predictors say about ACTRT1 p.Ser345Thr (c.1033T>A)?

AlphaMissense predicts ambiguous (score 0.397) — an in-silico prediction, not a clinical call.

ACTRT1 p.Ser345Thr

c.1033T>A · rs61745544 · VCV720066

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.397 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.5%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.397	ambiguous
REVEL	0.766	pathogenic-leaning
SaProt	LLR -12.32	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 6.3	phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,127 bp · p 0.013 · regional, not allelic
Overall
CADD	21.6	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 3.5% African / African-American · 1,972/56,355 alleles

Filtering AF 3.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.32%

Overall 0.186% 2,251/1,207,370 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.5%	29
Admixed American	0.251%	398
Remaining individualsnot grpmax-eligible	0.248%	403
Middle Eastern	0.161%	622
South Asian	0.0106%	9,425
European (non-Finnish)	0.0038%	26,316

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.Ser345Thr
Coding: c.1033T>A
MANE Select: NM_138289
dbSNP: rs61745544
Type: single nucleotide variant
Location: chrX:128051174 (GRCh38)
Structure: AlphaFold pLDDT 92.94
Residue 345: 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.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
ACTRT1 p.Arg231Ser 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-ser345thr (accessed [today's date]).

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