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

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates heart development and adipogenesis. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. The encoded protein may also be involved in the pathology of multiple cardiovascular diseases and human cancers. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 6MIM #607932

Orofacial cleft 11MIM #600625

UniProtNon-syndromic orofacial cleft 11

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · BMP4-related ocular growth disorder · AD · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

351

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

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 OE?0.07 (0.02–0.33)

0≤0.351.4

Missense OE?0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in BMP4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

529 rare PASS variants

Rare truncating (LoF)

1 in 9,500

26 rare PASS variants

Rare synonymous (reference)

1 in 240

223 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BMP4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 7,000
South Asian	~43k	1 in 69	1 in 5,400
Remaining (unassigned)	~30k	1 in 110	≈ 1 in 15,000
European (Finnish)	~27k	1 in 290	≈ 1 in 7,700
Admixed American	~22k	1 in 110	≈ 1 in 22,000
African / African American	~21k	1 in 110	≈ 1 in 16,000
East Asian	~20k	1 in 81	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 77	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓