Is ACTRT2 p.Ser113Cys (c.338C>G) pathogenic?

ACTRT2 p.Ser113Cys (c.338C>G) is classified Uncertain significance in ACTRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0821); Very rare (popmax 0.00246%, nfe).

How common is ACTRT2 p.Ser113Cys (c.338C>G) in the general population?

ACTRT2 p.Ser113Cys (c.338C>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about ACTRT2 p.Ser113Cys (c.338C>G)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

ACTRT2 p.Ser113Cys

c.338C>G · VCV4223327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -5.36	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 6	phastCons 0.83
Regional constraint	o/e 0.98	unconstrained · MANE · 1,130 bp · p 0.66 · regional, not allelic
Overall
CADD	24.3	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 0.00246% European (non-Finnish) · 29/1,180,046 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,613,598 alleles · very rare exomes 29/1,461,264 · genomes 0/152,334 · joint denominator

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.Ser113Cys
Coding: c.338C>G
MANE Select: NM_080431
Type: single nucleotide variant
Location: chr1:3022024 (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-ser113cys (accessed [today's date]).

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