Primary ovarian failure

Summary

Primary ovarian failure (MONDO:0005387) is a disease caused by variants in DMC1, KHDRBS1, and PRDM9, with 75 cohort genes (9 GWAS associations across 5 studies) and 75 clinical trials. The dominant Reactome pathway is Defective B3GALTL causes PpS (6 cohort genes). Top therapeutic interventions include prasterone, estradiol, and ethinyl estradiol.

At a glance

• Causal genes: DMC1 (GenCC Strong), KHDRBS1 (GenCC Strong), PRDM9 (GenCC Strong)
• Cohort genes: 75
• GWAS associations: 9
• ClinVar variants: 302
• Clinical trials: 75

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	primary ovarian failure
Mondo ID	MONDO:0005387
EFO	EFO:0004266
MeSH	D016649
Orphanet	619
DOID	DOID:5426
ICD-10-CM	E28.3
NCIT	C113352
SNOMED CT	370999003, 65846009
UMLS	C0085215
MedGen	38820
Is cancer (heuristic)	no

Also known as: premature ovarian failure · primary ovarian failure

Data availability: 302 ClinVar variants · 9 GWAS associations (5 studies) · 19 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › ovarian disorder › ovarian dysfunction › primary ovarian failure

Subtypes (4): premature menopause, acquired primary ovarian failure, inherited primary ovarian failure, autoimmune primary ovarian failure

Genetics & variants

GWAS landscape

9 GWAS associations across 5 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3847153	9e-08	RPS20P23 - RNU4-83P	?	1.42
rs9999820	3e-07	MAP9-AS1, NPY2R-AS1	G	7.52
rs4323056	4e-07	NPY2R-AS1	A	6.87
rs10793451	2e-06	ZNF485	T	7.14
rs2880418	2e-06	NPY2R-AS1	G	5.66
rs10058075	4e-06	DAB2	G	11.64
rs3966085	6e-06	UGT2A3 - SPOPLP2	G	28.89
rs4402990	8e-06	MAP9-AS1, NPY2R-AS1	C	4.19
rs6759058	9e-06	PRKCE	A	4.3

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST001284	Qin Y	2011	391	0	Association of 8q22.3 locus in Chinese Han with idiopathic premature ovarian failure (POF).
GCST000422	Knauff EA	2009	99	0	Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene.
GCST010976	Park J	2020	60	0	Association of an APBA3 Missense Variant with Risk of Premature Ovarian Failure in the Korean Female Population.
GCST005518	Brooke RJ	2018	27	0	A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.
GCST001406	Pyun JA	2012	24	0	LAMC1 gene is associated with premature ovarian failure.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	9

MAF distribution

Bucket	Variants
common (>=0.05)	9
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	8
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3847153	8	100800928	A>C,G,T	0.38	intron_variant	RPS20P23 - RNU4-83P	9e-08	Tier 4: intronic/intergenic
rs9999820	4	155197173	A>G	0.05	intron_variant	MAP9-AS1, NPY2R-AS1	3e-07	Tier 4: intronic/intergenic
rs4323056	4	155136200	G>A,C	0.05	intron_variant	NPY2R-AS1	4e-07	Tier 4: intronic/intergenic
rs10793451	10	43608447	T>A,C	0.05	intron_variant	ZNF485	2e-06	Tier 4: intronic/intergenic
rs2880418	4	155148727	A>C,G,T	0.05	intron_variant	NPY2R-AS1	2e-06	Tier 4: intronic/intergenic
rs10058075	5	39416192	G>C	0.05	intron_variant	DAB2	4e-06	Tier 4: intronic/intergenic
rs3966085	4	68964824	G>A	0.05	intergenic_variant	UGT2A3 - SPOPLP2	6e-06	Tier 4: intronic/intergenic
rs4402990	4	155187781	A>C,G,T	0.05	intron_variant	MAP9-AS1, NPY2R-AS1	8e-06	Tier 4: intronic/intergenic
rs6759058	2	45773347	A>C,G,T	0.05	intron_variant	PRKCE	9e-06	Tier 4: intronic/intergenic

ClinVar germline variants

302 retrieved; paginated sample, class counts are floors:

166 benign, 78 uncertain significance, 26 likely pathogenic, 21 conflicting classifications of pathogenicity, 6 pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
221776	GRCh37/hg19 Xq22.1-24(chrX:99931059-120328627)x1	ACSL4	Pathogenic	criteria provided, single submitter
221691	GRCh38/hg38 2p13.1(chr2:73601366-73673202)x1	ALMS1	Pathogenic	criteria provided, single submitter
929738	NM_207189.4(BRDT):c.1538del (p.Asp513fs)	BRDT	Pathogenic	criteria provided, single submitter
141818	NM_007194.4(CHEK2):c.1169A>C (p.Tyr390Ser)	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221719	GRCh37/hg19 8p23.1(chr8:8131816-12249050)x1	PINX1	Pathogenic	criteria provided, single submitter
92800	NM_000303.3(PMM2):c.323C>T (p.Ala108Val)	PMM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375672	NM_152524.6(SGO2):c.1453_1454del (p.Glu485fs)	SGO2	Pathogenic	no assertion criteria provided
929755	NM_001282717.2(STAG3):c.1069C>T (p.Arg357Ter)	STAG3	Pathogenic	criteria provided, single submitter
929783	NM_006988.5(ADAMTS1):c.1304C>A (p.Ser435Tyr)	ADAMTS1	Likely pathogenic	criteria provided, single submitter
929750	NM_197941.4(ADAMTS6):c.2840G>A (p.Arg947Gln)	ADAMTS6	Likely pathogenic	criteria provided, single submitter
221753	GRCh37/hg19 15q25.2(chr15:83213963-84811815)x1	ADAMTSL3	Likely pathogenic	criteria provided, single submitter
929787	NM_002025.4(AFF2):c.3203C>G (p.Ser1068Trp)	AFF2	Likely pathogenic	criteria provided, single submitter
929747	NM_001134.3(AFP):c.1822G>A (p.Gly608Arg)	AFP	Likely pathogenic	criteria provided, single submitter
929759	NM_001317056.2(ATG9B):c.1480G>T (p.Glu494Ter)	ATG9B	Likely pathogenic	criteria provided, single submitter
929751	NM_001718.6(BMP6):c.409C>A (p.Leu137Met)	BMP6	Likely pathogenic	criteria provided, single submitter
929778	NM_001717.4(BNC1):c.2273C>T (p.Thr758Ile)	BNC1	Likely pathogenic	criteria provided, single submitter
929785	NM_033656.4(BRWD1):c.656G>A (p.Arg219His)	BRWD1	Likely pathogenic	criteria provided, single submitter
221737	GRCh38/hg38 10q26.3(chr10:133443259-133566207)x1	CYP2E1	Likely pathogenic	criteria provided, single submitter
929761	NM_021240.4(DMRT3):c.1327C>T (p.Pro443Ser)	DMRT3	Likely pathogenic	criteria provided, single submitter
929745	NM_138815.4(DPPA2):c.833T>C (p.Leu278Ser)	DPPA2	Likely pathogenic	criteria provided, single submitter
929753	NM_000876.4(IGF2R):c.451C>T (p.His151Tyr)	IGF2R	Likely pathogenic	criteria provided, single submitter
134612	NM_002253.4(KDR):c.724C>T (p.Leu242Phe)	KDR	Likely pathogenic	criteria provided, single submitter
929733	NM_006559.3(KHDRBS1):c.1262C>T (p.Pro421Leu)	KHDRBS1	Likely pathogenic	criteria provided, single submitter
929735	NM_003579.4(RAD54L):c.1883A>C (p.Glu628Ala)	LRRC41	Likely pathogenic	criteria provided, single submitter
929736	NM_003579.4(RAD54L):c.1900C>T (p.Arg634Cys)	LRRC41	Likely pathogenic	criteria provided, single submitter
812128	GRCh37/hg19 4q31.3(chr4:154316483-154325120)	MND1	Likely pathogenic	criteria provided, single submitter
929756	NM_001436401.1(NOBOX):c.1089G>C (p.Lys363Asn)	NOBOX	Likely pathogenic	criteria provided, single submitter
929757	NM_000603.5(NOS3):c.172C>T (p.Pro58Ser)	NOS3	Likely pathogenic	criteria provided, single submitter
929758	NM_000603.5(NOS3):c.505G>A (p.Glu169Lys)	NOS3	Likely pathogenic	criteria provided, single submitter
929748	NM_000949.7(PRLR):c.851T>G (p.Leu284Trp)	PRLR	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 58 · Orphanet: 50 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BMPR2	Definitive	Autosomal dominant	pulmonary hypertension, primary, 1	6
DMC1	Strong	Autosomal recessive	primary ovarian failure	3
HID1	Strong	Autosomal recessive	primary ovarian failure	6
KHDRBS1	Strong	Autosomal dominant	primary ovarian failure
PRDM9	Strong	Autosomal dominant	primary ovarian failure
BMPR1A	Moderate	Autosomal dominant	primary ovarian failure	12
BUB1B	Moderate	Autosomal recessive	primary ovarian failure	8
DAZL	Moderate	Autosomal dominant	primary ovarian failure	2
EIF4ENIF1	Moderate	Autosomal dominant	primary ovarian failure
FANCI	Moderate	Autosomal recessive	primary ovarian failure	6
HELQ	Moderate	Autosomal dominant	primary ovarian failure
NANOS3	Moderate	Semidominant	primary ovarian failure
POLR2C	Moderate	Autosomal dominant	primary ovarian failure
POLR3H	Moderate	Autosomal recessive	primary ovarian failure	2
REC8	Moderate	Autosomal recessive	primary ovarian failure
ZNF483	Moderate	Autosomal dominant	primary ovarian failure
DACH2	Limited	Autosomal dominant	primary ovarian failure
PGRMC1	Limited	Autosomal dominant	primary ovarian failure	2
POU5F1	Limited	Autosomal dominant	primary ovarian failure
RAD51B	Limited	Autosomal recessive	primary ovarian failure

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMPR1A	Orphanet:157794	Hereditary mixed polyposis syndrome
BMPR1A	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
BMPR1A	Orphanet:440437	Familial colorectal cancer Type X
BMPR1A	Orphanet:79076	Juvenile polyposis of infancy
BMPR2	Orphanet:275777	Heritable pulmonary arterial hypertension
BMPR2	Orphanet:275786	Drug- or toxin-induced pulmonary arterial hypertension
BMPR2	Orphanet:31837	Pulmonary venoocclusive disease
BUB1B	Orphanet:1052	Mosaic variegated aneuploidy syndrome
PGRMC1	Orphanet:98994	Total early-onset cataract
FANCI	Orphanet:84	Fanconi anemia
POLR3H	Orphanet:243	46,XX gonadal dysgenesis
BMP6	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
SEMA5A	Orphanet:281	Monosomy 5p syndrome
SFPQ	Orphanet:319308	MiT family translocation renal cell carcinoma
BNC1	Orphanet:243	46,XX gonadal dysgenesis
STAG3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
TSPAN7	Orphanet:777	X-linked non-syndromic intellectual disability
BRWD1	Orphanet:244	Primary ciliary dyskinesia
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
XPNPEP2	Orphanet:100057	Renin-angiotensin-aldosterone system-blocker-induced angioedema
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
BCO1	Orphanet:199285	Hereditary hypercarotenemia and vitamin A deficiency
FMN2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
MRPS22	Orphanet:137908	Hypotonia with lactic acidemia and hyperammonemia
MRPS22	Orphanet:243	46,XX gonadal dysgenesis
SIRT6	Orphanet:580933	Lethal brain and heart developmental defects
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
SCARB1	Orphanet:181428	Familial Hyperalphalipoproteinemia
LARS2	Orphanet:528091	Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
LARS2	Orphanet:642945	Perrault syndrome type 1
LARS2	Orphanet:642976	Perrault syndrome type 2
CHSY1	Orphanet:363417	Temtamy preaxial brachydactyly syndrome

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HID1	HGNC:15736	ENSG00000167861	Q8IV36	Protein HID1	gencc,clinvar
REC8	HGNC:16879	ENSG00000100918	O95072	Meiotic recombination protein REC8 homolog	gencc,clinvar
KHDRBS1	HGNC:18116	ENSG00000121774	Q07666	KH domain-containing, RNA-binding, signal transduction-associated protein 1	gencc,clinvar
NANOS3	HGNC:22048	ENSG00000187556	P60323	Nanos homolog 3	gencc,clinvar
DMC1	HGNC:2927	ENSG00000100206	Q14565	Meiotic recombination protein DMC1/LIM15 homolog	gencc,clinvar
BMPR1A	HGNC:1076	ENSG00000107779	P36894	Bone morphogenetic protein receptor type-1A	gencc
BMPR2	HGNC:1078	ENSG00000204217	Q13873	Bone morphogenetic protein receptor type-2	gencc
BUB1B	HGNC:1149	ENSG00000156970	O60566	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	gencc
PRDM9	HGNC:13994	ENSG00000164256	Q9NQV7	Histone-lysine N-methyltransferase PRDM9	gencc
PGRMC1	HGNC:16090	ENSG00000101856	O00264	Membrane-associated progesterone receptor component 1	gencc
EIF4ENIF1	HGNC:16687	ENSG00000184708	Q9NRA8	Eukaryotic translation initiation factor 4E transporter	gencc
DACH2	HGNC:16814	ENSG00000126733	Q96NX9	Dachshund homolog 2	gencc
HELQ	HGNC:18536	ENSG00000163312	Q8TDG4	Helicase POLQ-like	gencc
ZNF483	HGNC:23384	ENSG00000173258	Q8TF39	Zinc finger protein 483	gencc
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	gencc
DAZL	HGNC:2685	ENSG00000092345	Q92904	Deleted in azoospermia-like	gencc
POLR3H	HGNC:30349	ENSG00000100413	Q9Y535	DNA-directed RNA polymerase III subunit RPC8	gencc
POLR2C	HGNC:9189	ENSG00000102978	P19387	DNA-directed RNA polymerase II subunit RPB3	gencc
POU5F1	HGNC:9221	ENSG00000204531	Q01860	POU domain, class 5, transcription factor 1	gencc
RAD51B	HGNC:9822	ENSG00000182185	O15315	DNA repair protein RAD51 homolog 2	gencc
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	clinvar
BMP6	HGNC:1073	ENSG00000153162	P22004	Bone morphogenetic protein 6	clinvar
SEMA5A	HGNC:10736	ENSG00000112902	Q13591	Semaphorin-5A	clinvar
SFPQ	HGNC:10774	ENSG00000116560	P23246	Splicing factor, proline- and glutamine-rich	clinvar
BNC1	HGNC:1081	ENSG00000169594	Q01954	Zinc finger protein basonuclin-1	clinvar
SLC24A2	HGNC:10976	ENSG00000155886	Q9UI40	Sodium/potassium/calcium exchanger 2	clinvar
BRD3	HGNC:1104	ENSG00000169925	Q15059	Bromodomain-containing protein 3	clinvar
BRDT	HGNC:1105	ENSG00000137948	Q58F21	Bromodomain testis-specific protein	clinvar
SOAT1	HGNC:11177	ENSG00000057252	P35610	Sterol O-acyltransferase 1	clinvar
STAG3	HGNC:11356	ENSG00000066923	Q9UJ98	Cohesin subunit SA-3	clinvar
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	clinvar
THBS1	HGNC:11785	ENSG00000137801	P07996	Thrombospondin-1	clinvar
TSPAN7	HGNC:11854	ENSG00000156298	P41732	Tetraspanin-7	clinvar
TOP3B	HGNC:11993	ENSG00000100038	O95985	DNA topoisomerase 3-beta-1	clinvar
UGT2B15	HGNC:12546	ENSG00000196620	P54855	UDP-glucuronosyltransferase 2B15	clinvar
BRWD1	HGNC:12760	ENSG00000185658	Q9NSI6	Bromodomain and WD repeat-containing protein 1	clinvar
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar
XPNPEP2	HGNC:12823	ENSG00000122121	O43895	Xaa-Pro aminopeptidase 2	clinvar
ZNF92	HGNC:13168	ENSG00000146757	Q03936	Zinc finger protein 92	clinvar
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	clinvar
CLEC4C	HGNC:13258	ENSG00000198178	Q8WTT0	C-type lectin domain family 4 member C	clinvar
BCO1	HGNC:13815	ENSG00000135697	Q9HAY6	Beta,beta-carotene 15,15’-dioxygenase	clinvar
DMRT3	HGNC:13909	ENSG00000064218	Q9NQL9	Doublesex- and mab-3-related transcription factor 3	clinvar
FMN2	HGNC:14074	ENSG00000155816	Q9NZ56	Formin-2	clinvar
NLGN1	HGNC:14291	ENSG00000169760	Q8N2Q7	Neuroligin-1	clinvar
C1QTNF6	HGNC:14343	ENSG00000133466	Q9BXI9	Complement C1q tumor necrosis factor-related protein 6	clinvar
CDRT15	HGNC:14395	ENSG00000223510	Q96T59	CMT1A duplicated region transcript 15 protein	clinvar
MRPS22	HGNC:14508	ENSG00000175110	P82650	Small ribosomal subunit protein mS22	clinvar
IMMP2L	HGNC:14598	ENSG00000184903	Q96T52	Mitochondrial inner membrane protease subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HID1	Protein HID1	May play an important role in the development of cancers in a broad range of tissues.
REC8	Meiotic recombination protein REC8 homolog	Required during meiosis for separation of sister chromatids and homologous chromosomes.
KHDRBS1	KH domain-containing, RNA-binding, signal transduction-associated protein 1	Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors.
NANOS3	Nanos homolog 3	Plays a role in the maintenance of the undifferentiated state of germ cells regulating the spermatogonia cell cycle and inducing a prolonged transit in G1 phase.
DMC1	Meiotic recombination protein DMC1/LIM15 homolog	Participates in meiotic recombination, specifically in homologous strand assimilation, which is required for the resolution of meiotic double-strand breaks.
BMPR1A	Bone morphogenetic protein receptor type-1A	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
BMPR2	Bone morphogenetic protein receptor type-2	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
BUB1B	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	Essential component of the mitotic checkpoint.
PRDM9	Histone-lysine N-methyltransferase PRDM9	Histone methyltransferase that sequentially mono-, di-, and tri-methylates both ‘Lys-4’ (H3K4) and ‘Lys-36’ (H3K36) of histone H3 to produce respectively trimethylated ‘Lys-4’ (H3K4me3) and trimethylated ‘Lys-36’ (H3K36me3) histone H3 and…
PGRMC1	Membrane-associated progesterone receptor component 1	Component of a progesterone-binding protein complex.
EIF4ENIF1	Eukaryotic translation initiation factor 4E transporter	EIF4E-binding protein that regulates translation and stability of mRNAs in processing bodies (P-bodies).
DACH2	Dachshund homolog 2	Transcription factor that is involved in regulation of organogenesis.
HELQ	Helicase POLQ-like	Single-stranded 3’-5’ DNA helicase that plays a key role in homology-driven double-strand break (DSB) repair.
ZNF483	Zinc finger protein 483	May be involved in transcriptional regulation.
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…
DAZL	Deleted in azoospermia-like	RNA-binding protein, which is essential for gametogenesis in both males and females.
POLR3H	DNA-directed RNA polymerase III subunit RPC8	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
POLR2C	DNA-directed RNA polymerase II subunit RPB3	Core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates.
POU5F1	POU domain, class 5, transcription factor 1	Transcription factor that binds to the octamer motif (5’-ATTTGCAT-3’).
RAD51B	DNA repair protein RAD51 homolog 2	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
BMP6	Bone morphogenetic protein 6	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation.
SEMA5A	Semaphorin-5A	Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate prot…
SFPQ	Splicing factor, proline- and glutamine-rich	DNA- and RNA binding protein, involved in several nuclear processes.
BNC1	Zinc finger protein basonuclin-1	Transcriptional activator.
SLC24A2	Sodium/potassium/calcium exchanger 2	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
BRD3	Bromodomain-containing protein 3	Chromatin reader that recognizes and binds acetylated histones, thereby controlling gene expression and remodeling chromatin structures.
BRDT	Bromodomain testis-specific protein	Testis-specific chromatin protein that specifically binds histone H4 acetylated at ‘Lys-5’ and ‘Lys-8’ (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis.
SOAT1	Sterol O-acyltransferase 1	Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol.
STAG3	Cohesin subunit SA-3	Meiosis specific component of cohesin complex.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
THBS1	Thrombospondin-1	Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.
TSPAN7	Tetraspanin-7	May be involved in cell proliferation and cell motility.
TOP3B	DNA topoisomerase 3-beta-1	Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.
UGT2B15	UDP-glucuronosyltransferase 2B15	UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite’s water solubility, thereby facilitating excretion into eit…
BRWD1	Bromodomain and WD repeat-containing protein 1	May be a transcriptional activator.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
XPNPEP2	Xaa-Pro aminopeptidase 2	Membrane-bound metalloprotease which catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro.
ZNF92	Zinc finger protein 92	May be involved in transcriptional regulation.
C3	Complement C3	Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adapt…
CLEC4C	C-type lectin domain family 4 member C	Lectin-type cell surface receptor which may play a role in antigen capturing by dendritic cells.
BCO1	Beta,beta-carotene 15,15’-dioxygenase	Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.
DMRT3	Doublesex- and mab-3-related transcription factor 3	Probable transcription factor that plays a role in configuring the spinal circuits controlling stride in vertebrates.
FMN2	Formin-2	Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization.
NLGN1	Neuroligin-1	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
IMMP2L	Mitochondrial inner membrane protease subunit 2	Catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space.
OR4K1	Olfactory receptor 4K1	Odorant receptor.
OR8J1	Olfactory receptor 8J1	Odorant receptor.
SIRT6	NAD-dependent protein deacylase sirtuin-6	NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging.

Protein-family classification

Druggable: 24 · Difficult: 15 · Unknown: 36 · Druggable fraction: 0.32

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	2	7.2×	0.320
Kinase	5	1.9×	0.570
Enzyme (other)	9	1.4×	0.570
Scaffold/PPI	6	1.4×	0.665
Ion channel	1	1.5×	0.764
GPCR	4	1.3×	0.764
Transcription factor	9	1.0×	0.764
Protease	2	1.0×	0.764
Other/Unknown	36	0.9×	0.930
Antibody/Immunoglobulin	1	0.4×	0.930

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HID1	Other/Unknown	no		HID1/Ecm30
REC8	Other/Unknown	no		Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C
KHDRBS1	Other/Unknown	no		KH_dom, Sam68-YY, Qua1_dom
NANOS3	Transcription factor	no		Nanos/Xcar2, Znf_nanos-typ, Nanos_sf
DMC1	Transcription factor	no		AAA+_ATPase, DNA_repair_Rad51/TF_NusA_a-hlx, Dmc1
BMPR1A	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
BMPR2	Kinase	yes		TGFB_receptor, Activin_recp, Prot_kinase_dom
BUB1B	Kinase	yes	2.7.11.1	Kinase-like_dom_sf, Mad3/Bub1_I, Bub1/Mad3
PRDM9	Transcription factor	no	2.1.1.359	SET_dom, KRAB, aKRAB
PGRMC1	Other/Unknown	no		Cyt_B5-like_heme/steroid-bd, Cyt_B5-like_heme/steroid_sf, MAPR/NEUFC/NENF-like
EIF4ENIF1	Other/Unknown	no		eIF4E-T
DACH2	Other/Unknown	no		SKI/SNO/DAC, DNA-bd_dom_put_sf, Ski_DNA-bd_sf
HELQ	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
ZNF483	Transcription factor	no		KRAB, SCAN_dom, Znf_C2H2_type
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
DAZL	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
POLR3H	Other/Unknown	no		RNAP_E/RPC8, Rpb7-like_N, NA-bd_OB-fold
POLR2C	Other/Unknown	no		DNA-dir_RNA_pol_30-40kDasu_CS, DNA-dir_RNA_pol_insert, DNA-dir_RNA_pol_RpoA/D/Rpb3
POU5F1	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
RAD51B	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
BMP6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SEMA5A	Scaffold/PPI	no		TSP1_rpt, Semap_dom, Plexin_repeat
SFPQ	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, NOPS
BNC1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Disconnected-like
SLC24A2	Other/Unknown	no		K/Na/Ca-exchanger, NaCa_Exmemb, NCX_ion-bd_dom_sf
BRD3	Other/Unknown	no		Bromodomain, Bromodomain_CS, NET_dom
BRDT	Other/Unknown	no		Bromodomain, Bromodomain_CS, NET_dom
SOAT1	Enzyme (other)	yes	2.3.1.26	MBOAT_fam, Oat_ACAT_DAG_ARE, Sterol_acyltranf_meta
STAG3	Other/Unknown	no		STAG, ARM-type_fold, SCD
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
THBS1	Other/Unknown	no		EGF, TSP1_rpt, VWF_dom
TSPAN7	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
TOP3B	Other/Unknown	no		Topo_IA, Topo_IA_2, Topo_IA_DNA-bd_dom
UGT2B15	Enzyme (other)	yes	2.4.1.17	UDP_glucos_trans, UDP_glycos_trans_CS, UDP-glycosyltransferase
BRWD1	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
XPNPEP2	Protease	yes	3.4.11.9	Creatinase_N, Pept_M24, Peptidase_M24B_aminopep-P_CS
ZNF92	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
CLEC4C	Other/Unknown	no		C-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
BCO1	Enzyme (other)	yes	1.13.11.63	Carotenoid_Oase
DMRT3	Other/Unknown	no		DM_DNA-bd, DMA, UBA-like_sf
FMN2	Other/Unknown	no		DEP_dom, FH2_Formin, FH2_Formin_sf
NLGN1	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS
C1QTNF6	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
CDRT15	Other/Unknown	no
MRPS22	Other/Unknown	no		Ribosomal_mS22
IMMP2L	Protease	yes		Pept_S26A_signal_pept_1, Peptidase_S26, Pept_S26A_signal_pept_1_CS

Expression context

Cohort genes with no expression data: 0.

66 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	4
moderate (6-20)	0
broad (>20)	71
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	10
primordial germ cell in gonad	9
ventricular zone	9
male germ line stem cell (sensu Vertebrata) in testis	8
buccal mucosa cell	7
cortical plate	6
oocyte	6
endothelial cell	6
prefrontal cortex	5
calcaneal tendon	5
ganglionic eminence	4
right testis	4
adrenal tissue	4
left testis	4
right adrenal gland	4
right adrenal gland cortex	4
jejunal mucosa	4
colonic epithelium	4
adenohypophysis	3
germinal epithelium of ovary	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HID1	212	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
REC8	134	broad	marker	adenohypophysis, pituitary gland, ganglionic eminence
KHDRBS1	300	ubiquitous	marker	germinal epithelium of ovary, ganglionic eminence, cortical plate
NANOS3	129	broad	yes	primordial germ cell in gonad, prefrontal cortex, amygdala
DMC1	171	broad	marker	buccal mucosa cell, primordial germ cell in gonad, right testis
BMPR1A	284	ubiquitous	marker	secondary oocyte, calcaneal tendon, saphenous vein
BMPR2	271	ubiquitous	marker	visceral pleura, lower lobe of lung, tendon of biceps brachii
BUB1B	210	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
PRDM9	70	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, diaphragm, primordial germ cell in gonad
PGRMC1	301	ubiquitous	marker	seminal vesicle, caput epididymis, adrenal tissue
EIF4ENIF1	283	ubiquitous	marker	secondary oocyte, oocyte, left testis
DACH2	124	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
HELQ	248	ubiquitous	marker	calcaneal tendon, buccal mucosa cell, primordial germ cell in gonad
ZNF483	239	ubiquitous	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
DAZL	59	tissue_specific	marker	oocyte, secondary oocyte, primordial germ cell in gonad
POLR3H	232	ubiquitous	marker	prefrontal cortex, anterior cingulate cortex, right frontal lobe
POLR2C	298	ubiquitous	marker	islet of Langerhans, secondary oocyte, adenohypophysis
POU5F1	132	tissue_specific	marker	primordial germ cell in gonad, right uterine tube, metanephros cortex
RAD51B	193	ubiquitous	marker	sural nerve, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
BMP6	197	ubiquitous	marker	secondary oocyte, cartilage tissue, oocyte
SEMA5A	262	ubiquitous	marker	metanephric glomerulus, renal glomerulus, stromal cell of endometrium
SFPQ	295	ubiquitous	marker	ventricular zone, tendon of biceps brachii, ganglionic eminence
BNC1	117	broad	marker	germinal epithelium of ovary, parietal pleura, primordial germ cell in gonad
SLC24A2	110	broad	marker	endothelial cell, lateral nuclear group of thalamus, postcentral gyrus
BRD3	302	ubiquitous	marker	nipple, medial globus pallidus, globus pallidus
BRDT	116	tissue_specific	marker	left testis, right testis, testis
SOAT1	266	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
STAG3	185	broad	marker	oocyte, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 22.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR2C	6,325
WWOX	5,892
THBS1	5,731
SCARB1	5,484
ATG7	5,169
CHEK2	4,795
TOP3B	4,289
GOLPH3	4,106
BUB1B	4,042
WT1	3,938

Intra-cohort edges

A	B	Sources
ASTN2	NLGN1	string_interaction
ASTN2	SEMA5A	string_interaction
BCO1	SCARB1	string_interaction
BMP6	BMPR1A	biogrid_interaction, string_interaction
BMP6	BMPR2	string_interaction
BMPR1A	BMPR2	string_interaction
BRD3	BRDT	string_interaction
BRDT	POU5F1	biogrid_interaction
CHEK2	SFPQ	intact
CHST11	CHSY1	string_interaction
CHSY1	OR4F15	string_interaction
CLNK	WWOX	biogrid_interaction
DACH2	XPNPEP2	string_interaction
DAZL	EIF4ENIF1	biogrid_interaction
DAZL	NANOS3	string_interaction
DMC1	PRDM9	string_interaction
DMC1	REC8	string_interaction
FANCI	HELQ	biogrid_interaction
HELQ	RAD51B	biogrid_interaction, intact
REC8	STAG3	string_interaction
SCARB1	SOAT1	string_interaction
SCARB1	THBS1	string_interaction

Structural data

PDB: 42 · AlphaFold-only: 33 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS22	P82650	77
C3	P01024	75
BRD3	Q15059	48
SIRT6	Q8N6T7	45
CHEK2	O96017	38
POLR3H	Q9Y535	29
WT1	P19544	28
POLR2C	P19387	21
BRDT	Q58F21	21
POU5F1	Q01860	16
SFPQ	P23246	13
TOP3B	O95985	12
BMPR1A	P36894	11
THBS1	P07996	11
KHDRBS1	Q07666	10
DMC1	Q14565	10
RYR3	Q15413	10
BUB1B	O60566	9
FANCI	Q9NVI1	8
BMPR2	Q13873	7
PRDM9	Q9NQV7	5
RAD51B	O15315	5
BMP6	P22004	5
SOAT1	P35610	5
CLEC4C	Q8WTT0	5
SEMA5A	Q13591	4
AK3	Q9UIJ7	4
EIF4ENIF1	Q9NRA8	3
TG	P01266	3
ASTN2	O75129	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AADAC	P22760	95.64
XPNPEP2	O43895	91.91
B3GNT5	Q9BYG0	90.89
LARS2	Q15031	90.57
BCO1	Q9HAY6	90.03
CHST11	Q9NPF2	89.39
TSPAN7	P41732	89.18
OR8J1	Q8NGP2	89.15
OR4F15	Q8NGB8	88.07
ATG7	O95352	88.06
IMMP2L	Q96T52	87.66
HID1	Q8IV36	86.13
OR4A15	Q8NGL6	85.02
SCARB1	Q8WTV0	84.25
CHSY1	Q86X52	84.20
OR4K1	Q8NGD4	83.88
STAG3	Q9UJ98	78.46
C1QTNF6	Q9BXI9	77.42
DLEU7	Q6UYE1	75.45
HELQ	Q8TDG4	74.30
LRRC41	Q15345	71.96
ZNF92	Q03936	71.94
NANOS3	P60323	71.75
SLC24A2	Q9UI40	67.75
ADAMTSL3	P82987	65.99
REC8	O95072	65.16
DACH2	Q96NX9	62.69
DMRT3	Q9NQL9	57.72
DAZL	Q92904	57.38
CLNK	Q7Z7G1	56.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 732. Enrichment computed across 248 evidence-associated genes (163 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 163 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective B3GALTL causes PpS	6	11.4×	0.005	SEMA5A, THBS1, ADAMTSL3, ADAMTS1, ADAMTS5, ADAMTS6
O-glycosylation of TSR domain-containing proteins	6	11.1×	0.005	SEMA5A, THBS1, ADAMTSL3, ADAMTS1, ADAMTS5, ADAMTS6
Diseases associated with O-glycosylation of proteins	5	6.6×	0.168	SEMA5A, ADAMTSL3, ADAMTS1, ADAMTS5, ADAMTS6
O-linked glycosylation	6	5.3×	0.168	SEMA5A, ADAMTSL3, B3GNT5, ADAMTS1, ADAMTS5, ADAMTS6
NGF-independant TRKA activation	2	28.0×	0.180	ADORA2A, NTRK1
PTK6 Regulates Proteins Involved in RNA Processing	2	28.0×	0.180	KHDRBS1, SFPQ
Regulation of NPAS4 gene transcription	2	28.0×	0.180	KCNIP3, REST
Aspirin ADME	4	7.8×	0.180	UGT2B15, CYP2C19, CYP2E1, UGT2A3
Fanconi Anemia Pathway	4	6.8×	0.218	FANCI, ERCC4, FANCA, FANCC
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	5	4.9×	0.249	ADCY5, RICTOR, FYN, KDR, NOS3
Adherens junctions interactions	4	6.1×	0.273	CDH19, CADM2, AFDN, MOV10
Formyl peptide receptors bind formyl peptides and many other ligands	2	17.5×	0.327	FPR2, APP
Activation of TRKA receptors	1	70.1×	0.360	ADORA2A
Defective PMM2 causes PMM2-CDG	1	70.1×	0.360	PMM2
Defective CYP17A1 causes AH5	1	70.1×	0.360	CYP17A1
Defective CYP19A1 causes AEXS	1	70.1×	0.360	CYP19A1
Defective GALT can cause GALCT	1	70.1×	0.360	GALT
Beta-ketothiolase deficiency	1	70.1×	0.360	ACAT1
Signaling by Leptin	2	12.7×	0.360	SH2B1, LEPR
Regulation of CDH1 mRNA translation by microRNAs	2	12.7×	0.360	MOV10, MYC
CYP2E1 reactions	2	11.7×	0.360	CYP2C19, CYP2E1
Specification of primordial germ cells	2	10.8×	0.360	NANOS3, POU5F1
Paracetamol ADME	3	7.8×	0.360	UGT2B15, CYP2E1, ABCC4
Signaling by BMP	3	6.6×	0.360	BMPR1A, BMPR2, INHA
Amplification of signal from the kinetochores	4	4.8×	0.360	BUB1B, CENPL, SGO2, CENPP
Reproduction	4	4.7×	0.360	NANOS3, STAG3, MND1, MLH3
Diseases of glycosylation	5	4.0×	0.360	SEMA5A, ADAMTSL3, ADAMTS1, ADAMTS5, ADAMTS6
Meiotic recombination	5	4.0×	0.360	DMC1, PRDM9, MND1, MLH3, RAD51C
Signaling by TGFB family members	5	3.5×	0.360	BMPR1A, BMPR2, INHA, MOV10, MYC
Diseases of metabolism	6	3.0×	0.376	SEMA5A, ADAMTSL3, ADAMTS1, ADAMTS5, ADAMTS6, ACAT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 213 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
reciprocal meiotic recombination	7	18.5×	1e-04	REC8, DMC1, MND1, MLH3, RAD51C, RAD51B, RAD54L
modification of synaptic structure	2	79.1×	0.038	PGRMC1, REST
prostate gland growth	3	29.7×	0.038	CYP19A1, AR, PRLR
ovulation from ovarian follicle	3	26.4×	0.038	ADAMTS1, AFP, NOS3
female gamete generation	4	15.1×	0.038	DMC1, PRDM9, MCM9, GDF9
sister chromatid cohesion	4	14.4×	0.038	REC8, STAG3, DDX11, RAD51C
double-strand break repair via homologous recombination	8	5.9×	0.038	REC8, SFPQ, HELQ, MCM9, ERCC4, RAD51C, RAD51B, RAD54L
embryonic cleavage	3	23.7×	0.041	AATF, PADI6, NR5A2
positive regulation of SMAD protein signal transduction	5	9.0×	0.041	BMP6, BMPR1A, BMPR2, DAB2, SH2B1
olfactory nerve development	2	52.7×	0.066	CHD7, NTRK1
positive regulation of aldosterone biosynthetic process	2	52.7×	0.066	BMP6, DAB2
male meiosis I	4	10.9×	0.066	REC8, DMC1, BRDT, RAD51C
plasma lipoprotein particle clearance	2	39.6×	0.066	SCARB1, MSR1
double-strand break repair via synthesis-dependent strand annealing	2	39.6×	0.066	HELQ, RAD54L
calcium ion-regulated exocytosis of neurotransmitter	2	39.6×	0.066	RIMS2, DOC2B
positive regulation of heart growth	2	39.6×	0.066	WT1, ACACB
cellular response to norepinephrine stimulus	2	39.6×	0.066	APP, PRKD1
positive regulation of aldosterone secretion	2	39.6×	0.066	BMP6, DAB2
GTP metabolic process	3	15.8×	0.066	AK3, EFL1, AK4
neuron cell-cell adhesion	3	14.0×	0.066	NLGN1, ASTN2, NCAM2
positive regulation of synaptic transmission, GABAergic	3	14.0×	0.066	NLGN1, ADORA2A, PRKCE
astrocyte activation	3	14.0×	0.066	ADORA2A, FPR2, APP
mammary gland alveolus development	3	14.0×	0.066	AR, AREG, PRLR
positive regulation of endothelial cell chemotaxis	3	14.0×	0.066	SEMA5A, KDR, PRKD1
positive regulation of miRNA transcription	5	6.8×	0.066	BMPR1A, WT1, AR, MYC, NOTCH2
cognition	5	6.7×	0.066	CHL1, CHRNA7, CHD7, DGCR2, APP
xenobiotic metabolic process	7	4.9×	0.066	UGT2B15, AADAC, CYP2C19, CYP2E1, UGT2A3, ABCC4, AOX1
positive regulation of angiogenesis	8	4.3×	0.066	SEMA5A, THBS1, C3, CHRNA7, KDR, NOS3, NTRK1, PRKD1
regulation of gene expression	9	3.5×	0.066	PRDM9, CHD7, RICTOR, AFF2, APBA2, APP, MAP3K4, MYC (+1 more)
spermatogenesis	15	2.5×	0.066	REC8, KHDRBS1, NANOS3, DMC1, BNC1, IMMP2L, CYLC2, DAZL (+7 more)

Therapeutics

Drugs indicated for this disease

6 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Choriogonadotropin Alfa	Approved (phase 4)
Estradiol	Approved (phase 4)
Estradiol Valerate	Approved (phase 4)
Estrogens, Conjugated	Approved (phase 4)
Estrogens, Esterified	Approved (phase 4)
Follitropin	Approved (phase 4)
Filgrastim	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Goserelin, Medroxyprogesterone Acetate, Prasterone.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 11 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 97 of 248 evidence-associated genes (39%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BMPR1A	MOMELOTINIB
BMPR2	FEDRATINIB
BUB1B	CERITINIB
PGRMC1	ENCORAFENIB
POU5F1	FAMOTIDINE
BRDT	FEDRATINIB
SOAT1	PROGESTERONE
SIRT6	NIACINAMIDE
CHEK2	NERATINIB
AADAC	FLUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHEK2	30	4
BMPR2	19	4
BRDT	12	4
BMPR1A	11	4
BRD3	8	3
SIRT6	7	4
SOAT1	6	4
SCARB1	2	2
KHDRBS1	1	2
BUB1B	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
FEDRATINIB	4	BMPR2, BRDT
RUXOLITINIB	4	BMPR2
BOSUTINIB	4	BMPR2, CHEK2
DEUCRAVACITINIB	4	BMPR2
NINTEDANIB	4	BMPR2
SUNITINIB	4	BMPR2, CHEK2
CERITINIB	4	BUB1B
ENCORAFENIB	4	PGRMC1
FAMOTIDINE	4	POU5F1
FOSTAMATINIB	4	BRDT
PROGESTERONE	4	SOAT1
NIACINAMIDE	4	SIRT6
FLUVASTATIN	4	SIRT6
NERATINIB	4	CHEK2
BRIGATINIB	4	CHEK2
GEFITINIB	4	CHEK2
FLUTAMIDE	4	AADAC
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A, BMPR2, CHEK2
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
DOVITINIB	3	BMPR2, CHEK2
APABETALONE	3	BRD3, BRDT
VOLASERTIB	3	BRDT
DINACICLIB	3	BRDT
ALVOCIDIB	3	BRDT
QUERCETIN	3	SIRT6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CHEK2	690	Binding:687, Functional:2, ADMET:1
BRD3	639	Binding:614, Functional:20, ADMET:5
BRDT	348	Binding:330, Functional:14, ADMET:4
SIRT6	244	Binding:240, Functional:4
BMPR1A	169	Binding:166, ADMET:3
BMPR2	166	Binding:165, ADMET:1
SOAT1	136	Binding:127, Functional:8, ADMET:1
UGT2B15	74	ADMET:71, Binding:3
PRDM9	60	Binding:58, Functional:2
BRWD1	37	Binding:37
POU5F1	36	Binding:36
AADAC	20	ADMET:19, Binding:1
C3	15	Binding:15
BUB1B	12	Binding:12
ATG7	12	Binding:12
THBS1	8	Binding:8
KHDRBS1	7	Binding:7
SFPQ	7	Binding:7
XPNPEP2	7	Binding:4, ADMET:3
PGRMC1	4	Binding:4
SCARB1	4	Binding:4
CLEC4C	3	Binding:3
RYR3	2	Binding:2
FANCI	1	Binding:1
BMP6	1	Binding:1
SLC24A2	1	Functional:1
MRPS22	1	Binding:1
LARS2	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1A	2.7.10.2	non-specific protein-tyrosine kinase
BUB1B	2.7.11.1	non-specific serine/threonine protein kinase
PRDM9	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
HELQ	3.6.4.12	DNA helicase
SOAT1	2.3.1.26	sterol O-acyltransferase
UGT2B15	2.4.1.17	glucuronosyltransferase
XPNPEP2	3.4.11.9	Xaa-Pro aminopeptidase
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
BCO1	1.13.11.63	beta-carotene 15,15’-dioxygenase
SIRT6	2.3.1.B41
B3GNT5	2.4.1.206	lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
LARS2	6.1.1.4	leucine-tRNA ligase
CHSY1	2.4.1.175, 2.4.1.226	glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase, N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase
AK3	2.7.4.10	nucleoside-triphosphate-adenylate kinase
CHST11	2.8.2.5	chondroitin 4-sulfotransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BMPR1A	169
BMPR2	166
BRD3	639
BRDT	348
SOAT1	136
SIRT6	244
CHEK2	690

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
FEDRATINIB	4	BMPR2, BRDT
RUXOLITINIB	4	BMPR2
BOSUTINIB	4	BMPR2, CHEK2
DEUCRAVACITINIB	4	BMPR2
NINTEDANIB	4	BMPR2
SUNITINIB	4	BMPR2, CHEK2
CERITINIB	4	BUB1B
ENCORAFENIB	4	PGRMC1
FAMOTIDINE	4	POU5F1
FOSTAMATINIB	4	BRDT
NIACINAMIDE	4	SIRT6
FLUVASTATIN	4	SIRT6
NERATINIB	4	CHEK2
BRIGATINIB	4	CHEK2
GEFITINIB	4	CHEK2
FLUTAMIDE	4	AADAC
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A, BMPR2, CHEK2
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
DOVITINIB	3	BMPR2, CHEK2
APABETALONE	3	BRD3, BRDT
VOLASERTIB	3	BRDT
DINACICLIB	3	BRDT
ALVOCIDIB	3	BRDT
QUERCETIN	3	SIRT6

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	BMPR1A, BMPR2, BUB1B, PGRMC1, POU5F1, BRDT, SOAT1, SIRT6, CHEK2, AADAC
B	Phased (≥1) drug, not yet approved	3	KHDRBS1, BRD3, SCARB1
C	Druggable family + PDB, no drug	5	RYR3, UGT2B15, C3, ASTN2, AK3
D	Druggable family + AlphaFold only, no drug	13	HELQ, XPNPEP2, BCO1, IMMP2L, ADAMTSL3, OR4K1, OR8J1, OR4F15, OR4A15, B3GNT5 (+3 more)
E	Difficult family or no structure, no drug	44	HID1, REC8, NANOS3, DMC1, PRDM9, EIF4ENIF1, DACH2, ZNF483, FANCI, DAZL (+34 more)

Undrugged target profiles

62 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP6	1	BMPR1A, BMPR2
THBS1	8	SCARB1
BCO1	0	SCARB1
HID1	0	—
REC8	0	—
NANOS3	0	—
DMC1	0	—
PRDM9	60	—
EIF4ENIF1	0	—
DACH2	0	—
HELQ	0	—
ZNF483	0	—
FANCI	1	—
DAZL	0	—
POLR3H	0	—
POLR2C	0	—
RAD51B	0	—
RYR3	2	—
SEMA5A	0	—
SFPQ	7	—
BNC1	0	—
SLC24A2	1	—
STAG3	0	—
TG	0	—
TSPAN7	0	—
TOP3B	0	—
UGT2B15	74	—
BRWD1	37	—
WT1	0	—
WWOX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 75.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	39
PHASE1/PHASE2	13
PHASE4	6
PHASE2	6
PHASE1	5
EARLY_PHASE1	3
PHASE2/PHASE3	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT02467231	Not specified	ACTIVE_NOT_RECRUITING	Ovarian Reserve After Cancer: Longitudinal Effects
NCT03381300	Not specified	ACTIVE_NOT_RECRUITING	Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome
NCT04381299	Not specified	ACTIVE_NOT_RECRUITING	Will Autologous Platelet Rich Plasma Able To Restore Ovarian Function?
NCT04390308	Not specified	RECRUITING	Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation?

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PRASTERONE	4	2
ESTRADIOL	4	1
ETHINYL ESTRADIOL	4	1
FILGRASTIM	4	1
FOLLITROPIN	4	1
GONADORELIN ACETATE	4	1
LEUPROLIDE	4	1
MEDROXYPROGESTERONE ACETATE	4	1
NORETHINDRONE	4	1
PROGESTERONE	4	1
TRIPTORELIN	4	1
ORGANON	2	2
SOLIZMESTROCEL	2	1
CHEMBL1078369	0	1
CHEMBL31399	0	1
CHEMBL287148	0	1
CHEMBL2370644	0	1