GDF2

Chr 10AD

growth differentiation factor 2

Also known as: BMP-9, BMP9, HHT5

NCBI Gene: 2658 ENSG00000263761 UniProt: Q9UK05 OMIM: 605120

The encoded protein is a secreted TGF-beta superfamily ligand that acts as a potent inhibitor of angiogenesis and regulates cartilage and bone development through SMAD1 signaling in endothelial cells. Mutations cause hereditary hemorrhagic telangiectasia type 5, inherited in an autosomal dominant pattern. This gene shows low constraint against loss-of-function variants, suggesting tolerance to protein loss.

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 cartilage and bone development, angiogenesis and differentiation of cholinergic central nervous system neurons. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Telangiectasia, hereditary hemorrhagic, type 5MIM #615506

Clinical highlights

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.98

LOEUF

Mechanism· predicted

📖

GeneReview available — GDF2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.002

Z-score 1.63

OE 0.49 (0.27–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.46Z-score

OE missense 0.92 (0.83–1.02)

239 obs / 259.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.27–0.98)

0≤0.351.4

Missense OE?0.92 (0.83–1.02)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 6 / 12.1Missense obs/exp: 239 / 259.8Syn Z: -2.08

Background carrier burden — how many people carry a rare variant somewhere in GDF2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 95

566 rare PASS variants

Rare truncating (LoF)

1 in 6,200

49 rare PASS variants

Rare synonymous (reference)

1 in 150

292 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GDF2. 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 5,300
South Asian	~43k	1 in 78	1 in 4,800
Remaining (unassigned)	~30k	1 in 88	≈ 1 in 30,000
European (Finnish)	~27k	1 in 290	≈ 1 in 27,000
Admixed American	~22k	1 in 67	≈ 1 in 11,000
African / African American	~21k	1 in 99	≈ 1 in 9,300
East Asian	~20k	1 in 130	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 110	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 ↓