GDF6

Chr 8ADAR

growth differentiation factor 6

Also known as: BMP-13, BMP13, CDMP2, KFM, KFS, KFS1, KFSL, SGM1

NCBI Gene: 392255 ENSG00000156466 UniProt: Q6KF10 OMIM: 601147

GDF6 encodes a secreted growth factor of the TGF-beta superfamily that controls proliferation and differentiation in the retina, regulates apoptosis during retinal development, and is required for normal bone and joint formation in the limbs, skull, and axial skeleton. Mutations cause Klippel-Feil syndrome, Leber congenital amaurosis, microphthalmia with or without coloboma, and multiple synostoses syndrome with both autosomal dominant and autosomal recessive inheritance patterns. This gene is highly constrained against loss-of-function variation, reflecting its critical role in skeletal and ocular 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 is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Klippel-Feil syndrome 1, autosomal dominantMIM #118100

Leber congenital amaurosis 17MIM #615360

Microphthalmia with coloboma 6, digenicMIM #613703

Microphthalmia, isolated 4MIM #613094

Multiple synostoses syndrome 4MIM #617898

UniProtDeafness, autosomal recessive, 118, with cochlear aplasia

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Klippel-Feil syndrome 1, autosomal dominant; Leber congenital amaurosis 17 (+3); no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — GDF6

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?

0.22LOEUF

pLI 0.988

Z-score 3.39

OE 0.00 (0.00–0.22)

Highly constrained

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

Missense Constraint?

0.93Z-score

OE missense 0.83 (0.74–0.93)

204 obs / 245.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.22)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 13.4Missense obs/exp: 204 / 245.2Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in GDF6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

625 rare PASS variants

Rare truncating (LoF)

1 in 7,900

21 rare PASS variants

Rare synonymous (reference)

1 in 160

313 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GDF6. 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 210	1 in 13,000
South Asian	~43k	1 in 100	1 in 3,200
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 9,300
European (Finnish)	~27k	1 in 490	1 in 2,800
Admixed American	~22k	1 in 130	1 in 1,900
African / African American	~21k	1 in 100	none seen
East Asian	~20k	1 in 89	1 in 3,200
Ashkenazi Jewish	~13k	1 in 250	1 in 2,300
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 ↓