Is ACVR2B p.Pro352Ala (c.1054C>G) pathogenic?

ACVR2B p.Pro352Ala (c.1054C>G) is classified Uncertain significance in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.1726); Ultra-rare (popmax 0.016%, afr).

How common is ACVR2B p.Pro352Ala (c.1054C>G) in the general population?

ACVR2B p.Pro352Ala (c.1054C>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about ACVR2B p.Pro352Ala (c.1054C>G)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

ACVR2B p.Pro352Ala

c.1054C>G · VCV3485470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -6.09	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 7.7	GERP 1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 4,811 bp · p 9.8e-17 · regional, not allelic
Overall
CADD	22.5	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 0.016% African / African-American · 12/75,062 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.000743% 12/1,614,190 alleles · ultra-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.Pro352Ala
Coding: c.1054C>G
MANE Select: NM_001106
Type: single nucleotide variant
Location: chr3:38481445 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 352: the protein kinase domain

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

Similar variants

ACVR2B p.Pro352= Likely benign ★ same residue
ACVR2B c.*4984T>C Uncertain significance ★★ same type
ACVR2B c.*9473T>C Uncertain significance ★★ same type
ACVR2B p.Arg161Trp Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg163His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg21His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg309His Uncertain significance ★★ ⚠ same type
ACVR2B p.Arg482Gln Uncertain significance ★★ ⚠ same type

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-pro352ala (accessed [today's date]).

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