Is ACVR2B p.Glu111= (c.333A>G) pathogenic?

ACVR2B p.Glu111= (c.333A>G) is classified Benign in ACVR2B (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Common (popmax 61.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Glu111= (c.333A>G)?

ACVR2B p.Glu111= (c.333A>G) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

ACVR2B p.Glu111=

Q: How common is ACVR2B p.Glu111= (c.333A>G) in the general population?

ACVR2B p.Glu111= (c.333A>G) is common (popmax 61.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.333A>G · rs2070489 · VCV257468

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 61.6%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1.8, phastCons 1
Overall
CADD	8.781	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 61.6% European (non-Finnish) · 727,174/1,179,880 alleles

Filtering AF 61.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.5%

Overall 58.9% 950,251/1,613,688 alleles · common exomes 870,869/1,461,744 · genomes 79,382/151,944 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	61.6%	2
South Asian	58%	2
Remaining individualsnot grpmax-eligible	57%	2
Finnishnot grpmax-eligible	56.5%	2
Ashkenazi Jewishnot grpmax-eligible	55.5%	2
Admixed American	53.6%	2
Middle Eastern	50.8%	2
Amishnot grpmax-eligible	48.6%	2
East Asian	46.6%	2
African / African-American	34%	3

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.Glu111=
Coding: c.333A>G
MANE Select: NM_001106
dbSNP: rs2070489
Type: single nucleotide variant
Location: chr3:38477933 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 111: a β-strand

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-glu111 (accessed [today's date]).

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