Is ACTR5 p.Ile237Val (c.709A>G) pathogenic?

ACTR5 p.Ile237Val (c.709A>G) is classified Uncertain significance in ACTR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: likely benign (0.078); Ultra-rare (popmax 0.0114%, nfe).

How common is ACTR5 p.Ile237Val (c.709A>G) in the general population?

ACTR5 p.Ile237Val (c.709A>G) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about ACTR5 p.Ile237Val (c.709A>G)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

ACTR5 p.Ile237Val

c.709A>G · rs146997847 · VCV2404770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -7.51	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 7.9	GERP 0.81, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.57 · regional, not allelic
Overall
CADD	22.8	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 0.0114% European (non-Finnish) · 134/1,179,982 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00855% 138/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,806
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-American	0.00133%	74,936

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: ACTR5
Protein: p.Ile237Val
Coding: c.709A>G
MANE Select: NM_024855
dbSNP: rs146997847
Type: single nucleotide variant
Location: chr20:38752234 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.75 · 6 PDB
Residue 237: a β-strand

Full ACTR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR5 p.Ala11Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala13Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala14Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala235Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala253Thr Uncertain significance ★ ⚠ same type
ACTR5 p.Ala371Val Uncertain significance ★ ⚠ same type
ACTR5 p.Ala541Gly Uncertain significance ★ ⚠ same type
ACTR5 p.Arg210His 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/actr5-p-ile237val (accessed [today's date]).

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