BMP4

Chr 14AD

bone morphogenetic protein 4

Also known as: BMP2B, BMP2B1, MCOPS6, OFC11, ZYME

NCBI Gene: 652 ENSG00000125378 UniProt: P12644 OMIM: 112262

This protein is a secreted growth factor of the TGF-beta superfamily that regulates essential developmental processes including neurogenesis, vascular development, and tooth formation by binding to BMP receptors and activating SMAD transcription factors. Mutations cause autosomal dominant microphthalmia and orofacial clefts, affecting craniofacial and ocular development. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.33), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.332 OMIM phenotypes

Clinical Summary— BMP4

🧬

Gene-Disease Validity (ClinGen)

BMP4-related ocular growth disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 178 VUS of 320 total submissions

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — BMP4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.956

Z-score 3.25

OE 0.07 (0.02–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

1.01Z-score

OE missense 0.82 (0.73–0.92)

212 obs / 257.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.07 (0.02–0.33)

0≤0.351.4

Missense OE0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

LoF obs/exp: 1 / 14.2Missense obs/exp: 212 / 257.5Syn Z: 0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBMP4-related microphthalmia with brain and digit anomaliesLOFAD

0.4289th %ile

GOF

0.2796th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 41% of P/LP variants are LoF · LOEUF 0.33

DN1 literature citation

Literature Evidence

DNThe difference in resulting phenotypes between c. 130G>T, p.(Gly44Ter) and c.171dupC, p.(Glu58Argfs*17) may therefore reflect the ability of these truncated prodomains to form a complex with growth factor dimers and produce a dominant-negative effect.PMID:30568244

LOFHaploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.PMID:29299063

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.