Is ACTL10 p.Arg74Pro (c.221G>C) pathogenic?

ACTL10 p.Arg74Pro (c.221G>C) is classified Uncertain significance in ACTL10 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.2083); Ultra-rare (popmax 0.09%, amr).

How common is ACTL10 p.Arg74Pro (c.221G>C) in the general population?

ACTL10 p.Arg74Pro (c.221G>C) is ultra-rare (popmax 0.09%, amr) (gnomAD).

What do computational predictors say about ACTL10 p.Arg74Pro (c.221G>C)?

AlphaMissense predicts likely benign (score 0.2083) — an in-silico prediction, not a clinical call.

ACTL10 p.Arg74Pro

c.221G>C · VCV4221037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2083	likely benign
REVEL	0.714	pathogenic-leaning
SaProt	LLR -7.07	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 734 bp · p 0.0047 · regional, not allelic
Overall
CADD	23.4	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 0.09% Admixed American · 54/60,028 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.00509% 82/1,612,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.09%	1,112
Remaining individualsnot grpmax-eligible	0.0352%	2,840
African / African-American	0.00666%	15,010
European (non-Finnish)	8.48e-05%	1,179,915

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: ACTL10
Protein: p.Arg74Pro
Coding: c.221G>C
MANE Select: NM_001024675
Type: single nucleotide variant
Location: chr20:33667718 (GRCh38)
Gene constraint: LOEUF 1.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.57

Full ACTL10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL10 p.Ala136Val Uncertain significance ★ ⚠ same type
ACTL10 p.Ala176Pro Uncertain significance ★ ⚠ same type
ACTL10 p.Ala193Glu Uncertain significance ★ ⚠ same type
ACTL10 p.Ala193Pro Uncertain significance ★ ⚠ same type
ACTL10 p.Ala22Ser Uncertain significance ★ ⚠ same type
ACTL10 p.Ala24Val Uncertain significance ★ ⚠ same type
ACTL10 p.Ala2Gly Uncertain significance ★ ⚠ same type
ACTL10 p.Ala34Glu 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/actl10-p-arg74pro (accessed [today's date]).

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