Is ACTR2 p.Pro95Ser (c.283C>T) pathogenic?

ACTR2 p.Pro95Ser (c.283C>T) is classified Uncertain significance in ACTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.0923); Very rare (popmax 0.00133%, afr).

How common is ACTR2 p.Pro95Ser (c.283C>T) in the general population?

ACTR2 p.Pro95Ser (c.283C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTR2 p.Pro95Ser (c.283C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

ACTR2 p.Pro95Ser

c.283C>T · VCV4637158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.98, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 41 kb · p 8.6e-43 · regional, not allelic
Overall
CADD	24.2	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 0.00133% African / African-American · 1/74,956 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,334 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,956
European (non-Finnish)	0.000339%	294,911

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: ACTR2
Protein: p.Pro95Ser
Coding: c.283C>T
MANE Select: NM_005722
Type: single nucleotide variant
Location: chr2:65246647 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.96 · 5 PDB

Full ACTR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR2 c.159+2094A>G Uncertain significance ★ same type
ACTR2 p.Arg103Lys Uncertain significance ★ ⚠ same type
ACTR2 p.Gly135Ser Uncertain significance ★ ⚠ same type
ACTR2 p.Ile227Thr Uncertain significance ★ ⚠ same type
ACTR2 p.Ile291Val Uncertain significance ★ ⚠ same type
ACTR2 p.Ile342Met Uncertain significance ★ ⚠ same type
ACTR2 p.Leu197Phe Uncertain significance ★ ⚠ same type
ACTR2 p.Lys341Asn 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/actr2-p-pro95ser (accessed [today's date]).

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