Is ACVR2A p.Val261Met (c.781G>A) pathogenic?

ACVR2A p.Val261Met (c.781G>A) is classified Uncertain significance in ACVR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.0857); Ultra-rare (popmax 0.0143%, sas).

How common is ACVR2A p.Val261Met (c.781G>A) in the general population?

ACVR2A p.Val261Met (c.781G>A) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about ACVR2A p.Val261Met (c.781G>A)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

ACVR2A p.Val261Met

c.781G>A · rs562464467 · VCV2272936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -4.91	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 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 27 kb · p 6.6e-34 · regional, not allelic
Overall
CADD	21.8	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 0.0143% South Asian · 13/90,964 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.000868% 14/1,612,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,997
Remaining individualsnot grpmax-eligible	0.0016%	62,420

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: ACVR2A
Protein: p.Val261Met
Coding: c.781G>A
MANE Select: NM_001616
dbSNP: rs562464467
Type: single nucleotide variant
Location: chr2:147917391 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.20 · 5 PDB
Residue 261: a β-strand; the protein kinase domain

Full ACVR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR2A c.1347+1G>A Uncertain significance ★ same type
ACVR2A p.Ala157Val Uncertain significance ★ ⚠ same type
ACVR2A p.Ala4Val Uncertain significance ★ ⚠ same type
ACVR2A p.Arg162Gly Uncertain significance ★ ⚠ same type
ACVR2A p.Arg24Gly Uncertain significance ★ ⚠ same type
ACVR2A p.Arg363Gln Uncertain significance ★ ⚠ same type
ACVR2A p.Asn108Ser Uncertain significance ★ ⚠ same type
ACVR2A p.Asn332Thr 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/acvr2a-p-val261met (accessed [today's date]).

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