Is ACVR2B p.Arg309His (c.926G>A) pathogenic?

ACVR2B p.Arg309His (c.926G>A) is classified Uncertain significance in ACVR2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1278); Ultra-rare (popmax 0.0253%, afr); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Arg309His (c.926G>A)?

ACVR2B p.Arg309His (c.926G>A) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Arg309His (c.926G>A) in the general population?

ACVR2B p.Arg309His (c.926G>A) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

What do computational predictors say about ACVR2B p.Arg309His (c.926G>A)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

ACVR2B p.Arg309His

c.926G>A · rs138692827 · VCV579193

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -9.83	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 8.6	GERP -0.27, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 4,811 bp · p 9.8e-17 · regional, not allelic
Overall
CADD	26.0	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 0.0253% African / African-American · 19/75,068 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00198% 32/1,614,244 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,951
Admixed American	0.00167%	60,034
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,088
European (non-Finnish)	0.000847%	118,005

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.Arg309His
Coding: c.926G>A
MANE Select: NM_001106
dbSNP: rs138692827
Type: single nucleotide variant
Location: chr3:38479793 (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.Arg309Cys 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-arg309his (accessed [today's date]).

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