Is ACVR2B p.Ala34Thr (c.100G>A) pathogenic?

ACVR2B p.Ala34Thr (c.100G>A) is classified Uncertain significance in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.000169%, nfe); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Ala34Thr (c.100G>A)?

ACVR2B p.Ala34Thr (c.100G>A) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Ala34Thr (c.100G>A) in the general population?

ACVR2B p.Ala34Thr (c.100G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ACVR2B p.Ala34Thr (c.100G>A)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

ACVR2B p.Ala34Thr

c.100G>A · rs371756878 · VCV1983435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -7.38	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 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 837 bp · p 7.9e-06 · regional, not allelic
Overall
CADD	24.4	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 0.000169% European (non-Finnish) · 2/1,180,012 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,854 alleles · very rare

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.Ala34Thr
Coding: c.100G>A
MANE Select: NM_001106
dbSNP: rs371756878
Type: single nucleotide variant
Location: chr3:38477334 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 34: a disulfide bond

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.Ala34Val 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.Arg309His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg482Gln 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-ala34thr (accessed [today's date]).

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