Is ACTRT3 p.Arg43Ser (c.127C>A) pathogenic?

ACTRT3 p.Arg43Ser (c.127C>A) is classified Uncertain significance in ACTRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.1712); Ultra-rare (popmax 0.0216%, nfe).

How common is ACTRT3 p.Arg43Ser (c.127C>A) in the general population?

ACTRT3 p.Arg43Ser (c.127C>A) is ultra-rare (popmax 0.0216%, nfe) (gnomAD).

What do computational predictors say about ACTRT3 p.Arg43Ser (c.127C>A)?

AlphaMissense predicts likely benign (score 0.1712) — an in-silico prediction, not a clinical call.

ACTRT3 p.Arg43Ser

c.127C>A · rs146844941 · VCV2457478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0216%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1712	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -3.4
Regional constraint	o/e 0.98	unconstrained · MANE · 2,085 bp · p 0.65 · regional, not allelic
Overall
CADD	0.059	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 0.0216% European (non-Finnish) · 255/1,178,092 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0164% 263/1,605,340 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0216%	4,620
Remaining individualsnot grpmax-eligible	0.00803%	12,458
Admixed American	0.00338%	29,612
African / African-American	0.00138%	72,260

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: ACTRT3
Protein: p.Arg43Ser
Coding: c.127C>A
MANE Select: NM_032487
dbSNP: rs146844941
Type: single nucleotide variant
Location: chr3:169769394 (GRCh38)
Gene constraint: LOEUF 1.242 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.47

Full ACTRT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTRT3 p.Arg43His Uncertain significance ★ ⚠ same residue
ACTRT3 p.Ala108Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala257Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala315Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala318Ser Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala323Thr Uncertain significance ★ ⚠ same type
ACTRT3 p.Arg205Ser Uncertain significance ★ same type
ACTRT3 p.Arg25Trp 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/actrt3-p-arg43ser (accessed [today's date]).

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