Is ACVR2B p.Ser229Arg (c.687T>G) pathogenic?

ACVR2B p.Ser229Arg (c.687T>G) is classified Uncertain significance in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). AlphaMissense: likely pathogenic (0.7789); Very rare (popmax 0.00398%, nfe).

How common is ACVR2B p.Ser229Arg (c.687T>G) in the general population?

ACVR2B p.Ser229Arg (c.687T>G) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about ACVR2B p.Ser229Arg (c.687T>G)?

AlphaMissense predicts likely pathogenic (score 0.7789) — an in-silico prediction, not a clinical call.

ACVR2B p.Ser229Arg

c.687T>G · VCV4003190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7789	likely pathogenic
REVEL	0.468	indeterminate
SaProt	LLR -4.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7	GERP -4.1
Regional constraint	o/e 0.58	unconstrained · MANE · 4,811 bp · p 9.8e-17 · regional, not allelic
Overall
CADD	12.9	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 0.00398% European (non-Finnish) · 47/1,179,908 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00297% 48/1,613,668 alleles · very rare exomes 48/1,461,880 · genomes 0/151,788 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,104
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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: ACVR2B
Protein: p.Ser229Arg
Coding: c.687T>G
MANE Select: NM_001106
Type: single nucleotide variant
Location: chr3:38479148 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 229: an α-helix; the protein kinase domain

Full ACVR2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR2B c.*4984T>C Uncertain significance ★★ same type
ACVR2B c.*9473T>C Uncertain significance ★★ same type
ACVR2B p.Arg161Trp Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg163His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg21His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg309His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg482Gln Uncertain significance ★★ ⚠ same type
ACVR2B p.Gln246His 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/acvr2b-p-ser229arg (accessed [today's date]).

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