Is ACTR2 p.Met67Val (c.199A>G) pathogenic?

ACTR2 p.Met67Val (c.199A>G) is classified Uncertain significance in ACTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.134); Very rare (popmax 0.000424%, nfe).

How common is ACTR2 p.Met67Val (c.199A>G) in the general population?

ACTR2 p.Met67Val (c.199A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ACTR2 p.Met67Val (c.199A>G)?

AlphaMissense predicts likely benign (score 0.134) — an in-silico prediction, not a clinical call.

ACTR2 p.Met67Val

c.199A>G · VCV4637159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.134	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.75, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 41 kb · p 8.6e-43 · regional, not allelic
Overall
CADD	23.3	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 0.000424% European (non-Finnish) · 5/1,179,622 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,460,940 alleles · very rare

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.Met67Val
Coding: c.199A>G
MANE Select: NM_005722
Type: single nucleotide variant
Location: chr2:65246563 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.96 · 5 PDB
Residue 67: an α-helix

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-met67val (accessed [today's date]).

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