Is BMP2 p.Val228Ala (c.683T>C) pathogenic?

BMP2 p.Val228Ala (c.683T>C) is classified Uncertain significance in BMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.5945); Ultra-rare (popmax 0.0333%, amr); Associated with Inborn genetic diseases.

What condition is associated with BMP2 p.Val228Ala (c.683T>C)?

BMP2 p.Val228Ala (c.683T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BMP2 p.Val228Ala (c.683T>C) in the general population?

BMP2 p.Val228Ala (c.683T>C) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about BMP2 p.Val228Ala (c.683T>C)?

AlphaMissense predicts likely pathogenic (score 0.5945) — an in-silico prediction, not a clinical call.

BMP2 p.Val228Ala

c.683T>C · VCV3667391

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5945	likely pathogenic
REVEL	0.535	indeterminate
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,670 bp · p 0.13 · 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 0.0333% Admixed American · 20/59,996 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00124% 20/1,614,008 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: BMP2
Protein: p.Val228Ala
Coding: c.683T>C
MANE Select: NM_001200
Type: single nucleotide variant
Location: chr20:6778581 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.37 · 21 PDB
Residue 228: a UniProt-annotated variant site (in ssfsc1)

Full BMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP2 p.Val228Gly Uncertain significance ★ ⚠ same residue
BMP2 p.Val228Leu Uncertain significance ★ ⚠ same residue
BMP2 p.Val228Met Uncertain significance ★ same residue
BMP2 p.Arg215Gln Uncertain significance ★★ ⚠ same condition
BMP2 p.Arg291His Uncertain significance ★★ ⚠ same condition
BMP2 p.Arg6Cys Uncertain significance ★★ ⚠ same condition
BMP2 p.Glu234Gly Uncertain significance ★★ ⚠ same condition
BMP2 p.Glu235Asp 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/bmp2-p-val228ala (accessed [today's date]).

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