Is ACVR2B p.Arg40His (c.119G>A) pathogenic?

ACVR2B p.Arg40His (c.119G>A) is classified Benign/Likely benign in ACVR2B (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0849); Low-frequency (popmax 1.28%, afr); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Arg40His (c.119G>A)?

ACVR2B p.Arg40His (c.119G>A) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Arg40His (c.119G>A) in the general population?

ACVR2B p.Arg40His (c.119G>A) is low-frequency (popmax 1.28%, afr) (gnomAD).

What do computational predictors say about ACVR2B p.Arg40His (c.119G>A)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

ACVR2B p.Arg40His

c.119G>A · rs121434437 · VCV6858

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.439	indeterminate
SaProt	LLR -7.64	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 7.3	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 837 bp · p 7.9e-06 · regional, not allelic
Overall
CADD	26.2	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 1.28% African / African-American · 963/75,038 alleles

Filtering AF 1.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.0846% 1,366/1,614,162 alleles · low-frequency exomes 812/1,461,846 · genomes 554/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.28%	78
Middle Eastern	0.231%	433
Remaining individualsnot grpmax-eligible	0.13%	772
Admixed American	0.1%	1,000
European (non-Finnish)	0.0204%	4,896
Finnishnot grpmax-eligible	0.00469%	21,343
South Asian	0.00329%	30,363
East Asian	0.00223%	44,880

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.Arg40His
Coding: c.119G>A
MANE Select: NM_001106
dbSNP: rs121434437
Type: single nucleotide variant
Location: chr3:38477353 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 40: a UniProt-annotated variant site (in htx4)

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 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.Arg309His 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-arg40his (accessed [today's date]).

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