GDF9

Chr 5AR

growth differentiation factor 9

Also known as: POF14

NCBI Gene: 2661ENSG00000164404UniProt: O60383

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 ovarian function. Reduced expression of this gene may be associated with polycystic ovary syndrome and mutations in this gene may be more common in mothers of dizygotic twins. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Premature ovarian failure 14MIM #618014
AR
122
ClinVar variants
21
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— GDF9
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 84 VUS of 122 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.19LOEUF
pLI 0.000
Z-score 1.05
OE 0.70 (0.43–1.19)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.57Z-score
OE missense 1.10 (1.00–1.22)
259 obs / 234.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.43–1.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.10 (1.00–1.22)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 10 / 14.3Missense obs/exp: 259 / 234.6Syn Z: -0.57

ClinVar Variant Classifications

122 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic5
VUS84
Likely Benign8
Benign7
Conflicting2
16
Pathogenic
5
Likely Pathogenic
84
VUS
8
Likely Benign
7
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
15
0
16
Likely Pathogenic
3
1
1
0
5
VUS
1
76
6
1
84
Likely Benign
0
2
2
4
8
Benign
0
1
4
2
7
Conflicting
—2
Total481287122

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GDF9 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Premature ovarian failure 14

MIM #618014

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function.
Belli M et al.·Vitam Horm
2018Review
The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency.
Liu MN et al.·Hum Fertil (Camb)
2021Review
GDF9(His209GlnfsTer6/S428T) and GDF9(Q321X/S428T) bi-allelic variants caused female subfertility with defective follicle enlargement.
Duan Y et al.·Cell Commun Signal
2024
Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia.
Mo J et al.·Br J Haematol
2024Functional
Screening of premature ovarian insufficiency associated genes in Hungarian patients with next generation sequencing.
Illés A et al.·BMC Med Genomics
2024Cohort
Application of specific ELISAs for BMP15 and GDF9 to cumulus cell extracts from infertile women.
Krysta-Matter AE et al.·Mol Cell Endocrinol
2023
Genes governing premature ovarian failure.
Dixit H et al.·Reprod Biomed Online
2010Review
Oocyte-Secreted Serum Biomarkers GDF9 and BMP15 in Women with Endometriosis.
Shamsa A et al.·Reprod Sci
2023
Ovarian insufficiency and secondary amenorrhea in a patient with a novel variant within GDF9 gene.
Marinakis NM et al.·Menopause
2022Case report
GDF-9 and BMP-15 direct the follicle symphony.
Sanfins A et al.·J Assist Reprod Genet
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Application of CRISPR/Cas9 for GDF9 Gene Editing in Caprine Granulosa Cells: Effects on Receptor Signalling and FGF2 Response.
Anjali et al.·Reprod Domest Anim
2025
Genetic variation landscape of sheep GDF9 gene from global ewes breeds and their association with gestation days.
Liu P et al.·BMC Genomics
2025🔓 Open Access
Ovarian stage-dependent expression of GDF9, BMP15, and AMH in domestic cats.
Thatsanabunjong F et al.·Theriogenology
2026
Exploring the functional and structural impacts of high-risk nsSNPs in human BMP15 and GDF9 genes associated with premature ovarian failure: an in silico approach.
Navapour L et al.·J Biomol Struct Dyn
2025Functional
Efficient gene editing of BMP15, GDF9, and MSTN-but not the imprinted CLPG gene-in goat embryos via electrotransfection and handmade cloning.
Hajian M et al.·Funct Integr Genomics
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
In Vitro Fertilization

Effect of Super-GDF9 on CAPA-IVM of COCs From Small Antral Follicles

RECRUITING
NCT06766604Phase NAMỹ Đức HospitalStarted 2025-01-10
Super-GDF9 supplementation during CAPA-IVMConventional CAPA-IVM

External Resources

Links to major genomics databases and tools