Is ACTR3 p.Ile67Val (c.199A>G) pathogenic?

ACTR3 p.Ile67Val (c.199A>G) is classified Uncertain significance in ACTR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely benign (0.069); Very rare (popmax 0.00493%, nfe).

How common is ACTR3 p.Ile67Val (c.199A>G) in the general population?

ACTR3 p.Ile67Val (c.199A>G) is very rare (popmax 0.00493%, nfe) (gnomAD).

What do computational predictors say about ACTR3 p.Ile67Val (c.199A>G)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

ACTR3 p.Ile67Val

c.199A>G · rs763378050 · VCV2459469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00493%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -7.25	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 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 67 kb · p 2.4e-24 · regional, not allelic
Overall
CADD	22.2	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 0.00493% European (non-Finnish) · 58/1,176,752 alleles

Filtering AF 0.00387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00354%

Overall 0.00392% 63/1,607,386 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00493%	20,289
African / African-American	0.00402%	24,879
Remaining individualsnot grpmax-eligible	0.00322%	31,042

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: ACTR3
Protein: p.Ile67Val
Coding: c.199A>G
MANE Select: NM_005721
dbSNP: rs763378050
Type: single nucleotide variant
Location: chr2:113916982 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 5 PDB
Residue 67: an α-helix

Full ACTR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR3 p.Arg79Cys Uncertain significance ★ ⚠ same type
ACTR3 p.Asn260Ser Uncertain significance ★ ⚠ same type
ACTR3 p.Asn411Ser Uncertain significance ★ ⚠ same type
ACTR3 p.Gly3Glu Uncertain significance ★ ⚠ same type
ACTR3 p.His80Arg Uncertain significance ★ ⚠ same type
ACTR3 p.Ile253Ser Uncertain significance ★ ⚠ same type
ACTR3 p.Leu339Val Uncertain significance ★ ⚠ same type
ACTR3 p.Lys228Met 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/actr3-p-ile67val (accessed [today's date]).

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