Is ACVR2B p.Arg309Cys (c.925C>T) pathogenic?

ACVR2B p.Arg309Cys (c.925C>T) is classified Uncertain significance in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely benign (0.2229); Very rare (popmax 0.00549%, sas); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Arg309Cys (c.925C>T)?

ACVR2B p.Arg309Cys (c.925C>T) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Arg309Cys (c.925C>T) in the general population?

ACVR2B p.Arg309Cys (c.925C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about ACVR2B p.Arg309Cys (c.925C>T)?

AlphaMissense predicts likely benign (score 0.2229) — an in-silico prediction, not a clinical call.

ACVR2B p.Arg309Cys

c.925C>T · rs769170500 · VCV999038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.2229	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 4,811 bp · p 9.8e-17 · regional, not allelic
Overall
CADD	33.0	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 0.00549% South Asian · 5/91,080 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00186% 30/1,614,088 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,216
East Asian	0.00446%	22,445
African / African-American	0.004%	24,979
European (non-Finnish)	0.00169%	59,002

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.Arg309Cys
Coding: c.925C>T
MANE Select: NM_001106
dbSNP: rs769170500
Type: single nucleotide variant
Location: chr3:38479792 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 309: a turn; the protein kinase domain

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

Disease context

heterotaxy, visceral, 4, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACVR2B p.Arg309His Uncertain significance ★★ ⚠ same residue
ACVR2B c.*4984T>C Uncertain significance ★★ same condition
ACVR2B c.*9473T>C Uncertain significance ★★ same condition
ACVR2B p.Arg161Trp Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg163His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg21His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg482Gln Uncertain significance ★★ ⚠ same condition
ACVR2B p.Gln246His Uncertain significance ★★ ⚠ same condition

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-arg309cys (accessed [today's date]).

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