Premature menopause

Summary

Premature menopause (MONDO:0001119) is a disease with 51 cohort genes and 82 clinical trials. The dominant Reactome pathway is Meiosis (5 cohort genes). Top therapeutic interventions include prasterone, estradiol, and ethinyl estradiol.

At a glance

• Cohort genes: 51
• ClinVar variants: 74
• Clinical trials: 82

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	premature menopause
Mondo ID	MONDO:0001119
EFO	EFO:0009005
MeSH	D008594
DOID	DOID:10787
ICD-10-CM	E28.31
NCIT	C80099
SNOMED CT	237788002
UMLS	C0025322
MedGen	9963
Is cancer (heuristic)	no

Also known as: early menopause · POF · premature menopause · premature ovarian failure

Data availability: 74 ClinVar variants · 1 cell line.

Disease family

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

Related subtypes (3): acquired primary ovarian failure, inherited primary ovarian failure, autoimmune primary ovarian failure

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

74 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 11 pathogenic, 10 conflicting classifications of pathogenicity, 6 likely pathogenic, 5 pathogenic/likely pathogenic, 4 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684623	NM_001258392.3(CLPB):c.1167+5G>A	CLPB	Pathogenic	no assertion criteria provided
187786	NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
495049	NM_014239.4(EIF2B2):c.514C>T (p.Arg172Ter)	EIF2B2	Pathogenic	criteria provided, single submitter
495050	NM_014239.4(EIF2B2):c.818A>G (p.Lys273Arg)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981245	NM_001983.4(ERCC1):c.321+61_525+132del	ERCC1	Pathogenic	no assertion criteria provided
619039	NM_020207.7(ERCC6L2):c.2156del (p.Gly719fs)	ERCC6L2	Pathogenic	criteria provided, multiple submitters, no conflicts
1214015	NM_001171251.3(HROB):c.421del (p.Glu141fs)	HROB	Pathogenic/Likely pathogenic	no assertion criteria provided
869115	NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)	MSH4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495048	NM_002485.5(NBN):c.871C>T (p.Gln291Ter)	NBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65408	NM_178170.3(NEK8):c.1795C>T (p.Arg599Ter)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619046	NM_001171613.2(PREPL):c.614_688delinsTTTTA (p.Lys205fs)	PREPL	Pathogenic	no assertion criteria provided
619047	NC_000002.12:g.44277853_44353364del	PREPL	Pathogenic	no assertion criteria provided
1677243	NM_003722.5(TP63):c.290G>C (p.Arg97Pro)	TP63	Pathogenic	no assertion criteria provided
1677244	NM_003722.5(TP63):c.1939C>T (p.Arg647Cys)	TP63	Pathogenic	no assertion criteria provided
619065	NM_003722.5(TP63):c.1780C>T (p.Arg594Ter)	TP63	Pathogenic	no assertion criteria provided
619066	NM_003722.5(TP63):c.1794G>A (p.Trp598Ter)	TP63	Pathogenic	no assertion criteria provided
625854	GRCh37/hg19 Xq25-28(chrX:122757437-155208244)x1	APLN	Likely pathogenic	no assertion criteria provided
1706435	NM_015971.4(MRPS7):c.373A>T (p.Lys125Ter)	MRPS7	Likely pathogenic	criteria provided, single submitter
1214013	NM_001048205.2(REC8):c.1035_1036dup (p.Ala346fs)	REC8	Likely pathogenic	no assertion criteria provided
1214014	NM_001048205.2(REC8):c.624+1G>A	REC8	Likely pathogenic	no assertion criteria provided
1048096	NM_001282717.2(STAG3):c.1953_1955del (p.Leu652del)	STAG3	Likely pathogenic	criteria provided, single submitter
374000	NM_001282717.2(STAG3):c.2776C>T (p.Arg926Ter)	STAG3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
978472	NM_001983.4(ERCC1):c.466C>T (p.Arg156Trp)	ERCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241247	NM_018062.4(FANCL):c.1007_1009del (p.Ile336_Cys337delinsSer)	FANCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
869200	NM_004837.4(GGPS1):c.782G>A (p.Arg261His)	GGPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619069	NM_001098426.2(SMARCD2):c.93del (p.Ala32fs)	LOC130061409	Conflicting classifications of pathogenicity	no assertion criteria provided
141414	NM_005591.4(MRE11):c.305G>T (p.Gly102Val)	MRE11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1349478	NM_015971.4(MRPS7):c.536G>A (p.Arg179His)	MRPS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
553552	NM_000287.4(PEX6):c.2356C>T (p.Arg786Trp)	PEX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
10794	NM_024921.4(POF1B):c.986G>A (p.Arg329Gln)	POF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 75 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMPR1B	Orphanet:2098	Acromesomelic dysplasia, Grebe type
BMPR1B	Orphanet:2639	Fibular aplasia-complex brachydactyly syndrome
BMPR1B	Orphanet:93384	Brachydactyly type C
BMPR1B	Orphanet:93388	Brachydactyly type A1
BMPR1B	Orphanet:93396	Brachydactyly type A2
SOX3	Orphanet:3157	Septo-optic dysplasia spectrum
SOX3	Orphanet:393	46,XX testicular difference of sex development
SOX3	Orphanet:67045	X-linked intellectual disability with isolated growth hormone deficiency
SOX3	Orphanet:79495	X-linked congenital generalized hypertrichosis
SOX3	Orphanet:90695	Non-acquired panhypopituitarism
STAG1	Orphanet:502434	STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome
STAG3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
NEK8	Orphanet:294415	Renal-hepatic-pancreatic dysplasia
NEK8	Orphanet:730	Autosomal dominant polycystic kidney disease
NEK8	Orphanet:93591	Infantile nephronophthisis
MRPS7	Orphanet:457223	Syndromic sensorineural deafness due to combined oxidative phosphorylation defect
TP63	Orphanet:1072	Ankyloblepharon filiforme adnatum-cleft palate syndrome
TP63	Orphanet:141291	Cleft lip and alveolus
TP63	Orphanet:1896	EEC syndrome
TP63	Orphanet:199302	Isolated cleft lip
TP63	Orphanet:199306	Cleft lip/palate
TP63	Orphanet:2440	Isolated split hand-split foot malformation
TP63	Orphanet:69085	Limb-mammary syndrome
TP63	Orphanet:93930	Classic bladder exstrophy
TP63	Orphanet:978	ADULT syndrome
NEK9	Orphanet:464366	NEK9-related lethal skeletal dysplasia
NEK9	Orphanet:64754	Nevus comedonicus syndrome
GREM1	Orphanet:157794	Hereditary mixed polyposis syndrome
FANCL	Orphanet:84	Fanconi anemia
MCM9	Orphanet:444048	46,XX ovarian dysgenesis-short stature syndrome
ERCC6L2	Orphanet:319465	Inherited acute myeloid leukemia
ERCC6L2	Orphanet:401764	Pancytopenia-developmental delay syndrome
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
NUP107	Orphanet:2065	Galloway-Mowat syndrome
NUP107	Orphanet:243	46,XX gonadal dysgenesis
NUP107	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
PREPL	Orphanet:163690	Hypotonia-cystinuria syndrome
PREPL	Orphanet:163693	2p21 microdeletion syndrome
PREPL	Orphanet:238523	Atypical hypotonia-cystinuria syndrome
PREPL	Orphanet:369881	2p21 microdeletion syndrome without cystinuria
CLPB	Orphanet:445038	3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome
CLPB	Orphanet:486	Autosomal dominant severe congenital neutropenia
EIF2B2	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B2	Orphanet:157716	Late infantile CACH syndrome
EIF2B2	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B2	Orphanet:99853	Ovarioleukodystrophy
EIF2B2	Orphanet:99854	Cree leukoencephalopathy
ERCC1	Orphanet:1466	COFS syndrome
ERCC1	Orphanet:90322	Cockayne syndrome type 2

Cohort genes → proteins

51 cohort genes, 50 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	51

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMPR1B	HGNC:1077	ENSG00000138696	O00238	Bone morphogenetic protein receptor type-1B	clinvar
SOX3	HGNC:11199	ENSG00000134595	P41225	Transcription factor SOX-3	clinvar
STAG1	HGNC:11354	ENSG00000118007	Q8WVM7	Cohesin subunit SA-1	clinvar
STAG3	HGNC:11356	ENSG00000066923	Q9UJ98	Cohesin subunit SA-3	clinvar
TFAM	HGNC:11741	ENSG00000108064	Q00059	Transcription factor A, mitochondrial	clinvar
NEK8	HGNC:13387	ENSG00000160602	Q86SG6	Serine/threonine-protein kinase Nek8	clinvar
POF1B	HGNC:13711	ENSG00000124429	Q8WVV4	Protein POF1B	clinvar
PMEPA1	HGNC:14107	ENSG00000124225	Q969W9	Protein TMEPAI	clinvar
MRPS7	HGNC:14499	ENSG00000125445	Q9Y2R9	Small ribosomal subunit protein uS7m	clinvar
TP63	HGNC:15979	ENSG00000073282	Q9H3D4	Tumor protein 63	clinvar
CCNT2	HGNC:1600	ENSG00000082258	O60583	Cyclin-T2	clinvar
APLN	HGNC:16665	ENSG00000171388	Q9ULZ1	Apelin	clinvar
REC8	HGNC:16879	ENSG00000100918	O95072	Meiotic recombination protein REC8 homolog	clinvar
CDC7	HGNC:1745	ENSG00000097046	O00311	Cell division cycle 7-related protein kinase	clinvar
NEK9	HGNC:18591	ENSG00000119638	Q8TD19	Serine/threonine-protein kinase Nek9	clinvar
DDI1	HGNC:18961	ENSG00000170967	Q8WTU0	Protein DDI1 homolog 1	clinvar
CKB	HGNC:1991	ENSG00000166165	P12277	Creatine kinase B-type	clinvar
GREM1	HGNC:2001	ENSG00000166923	O60565	Gremlin-1	clinvar
FANCL	HGNC:20748	ENSG00000115392	Q9NW38	E3 ubiquitin-protein ligase FANCL	clinvar
CROCC	HGNC:21299	ENSG00000058453	Q5TZA2	Rootletin	clinvar
MCM9	HGNC:21484	ENSG00000111877	Q9NXL9	DNA helicase MCM9	clinvar
TTC16	HGNC:26536	ENSG00000167094	Q8NEE8	Tetratricopeptide repeat protein 16	clinvar
ERCC6L2	HGNC:26922	ENSG00000182150	Q5T890	DNA excision repair protein ERCC-6-like 2	clinvar
HROB	HGNC:28460	ENSG00000125319	Q8N3J3	Homologous recombination OB-fold protein	clinvar
CAMSAP2	HGNC:29188	ENSG00000118200	Q08AD1	Calmodulin-regulated spectrin-associated protein 2	clinvar
USP53	HGNC:29255	ENSG00000145390	Q70EK8	Ubiquitin carboxyl-terminal hydrolase 53	clinvar
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	clinvar
TOP1MT	HGNC:29787	ENSG00000184428	Q969P6	DNA topoisomerase I, mitochondrial	clinvar
NUP107	HGNC:29914	ENSG00000111581	P57740	Nuclear pore complex protein Nup107	clinvar
PREPL	HGNC:30228	ENSG00000138078	Q4J6C6	Prolyl endopeptidase-like	clinvar
UBR4	HGNC:30313	ENSG00000127481	Q5T4S7	E3 ubiquitin-protein ligase UBR4	clinvar
SSH1	HGNC:30579	ENSG00000084112	Q8WYL5	Protein phosphatase Slingshot homolog 1	clinvar
CLPB	HGNC:30664	ENSG00000162129	Q9H078	Mitochondrial disaggregase	clinvar
EIF2B2	HGNC:3258	ENSG00000119718	P49770	Translation initiation factor eIF2B subunit beta	clinvar
ERCC1	HGNC:3433	ENSG00000012061	P07992	DNA excision repair protein ERCC-1	clinvar
ESRRB	HGNC:3473	ENSG00000119715	O95718	Steroid hormone receptor ERR2	clinvar
ESRRG	HGNC:3474	ENSG00000196482	P62508	Estrogen-related receptor gamma	clinvar
CENPI	HGNC:3968	ENSG00000102384	Q92674	Centromere protein I	clinvar
TH2LCRR	HGNC:40495	ENSG00000223442		T helper type 2 locus control region associated RNA	clinvar
GGPS1	HGNC:4249	ENSG00000152904	O95749	Geranylgeranyl pyrophosphate synthase	clinvar
AMHR2	HGNC:465	ENSG00000135409	Q16671	Anti-Muellerian hormone type-2 receptor	clinvar
HERC1	HGNC:4867	ENSG00000103657	Q15751	Probable E3 ubiquitin-protein ligase HERC1	clinvar
FOXK2	HGNC:6036	ENSG00000141568	Q01167	Forkhead box protein K2	clinvar
MRE11	HGNC:7230	ENSG00000020922	P49959	Double-strand break repair protein MRE11	clinvar
MSH4	HGNC:7327	ENSG00000057468	O15457	MutS protein homolog 4	clinvar
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	clinvar
NTRK3	HGNC:8033	ENSG00000140538	Q16288	NT-3 growth factor receptor	clinvar
NUP155	HGNC:8063	ENSG00000113569	O75694	Nuclear pore complex protein Nup155	clinvar
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	clinvar
RAD50	HGNC:9816	ENSG00000113522	Q92878	DNA repair protein RAD50	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMPR1B	Bone morphogenetic protein receptor type-1B	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
SOX3	Transcription factor SOX-3	Transcription factor required during the formation of the hypothalamo-pituitary axis.
STAG1	Cohesin subunit SA-1	Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication.
STAG3	Cohesin subunit SA-3	Meiosis specific component of cohesin complex.
TFAM	Transcription factor A, mitochondrial	Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation.
NEK8	Serine/threonine-protein kinase Nek8	Required for renal tubular integrity.
POF1B	Protein POF1B	Plays a key role in the organization of epithelial monolayers by regulating the actin cytoskeleton.
PMEPA1	Protein TMEPAI	Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression.
TP63	Tumor protein 63	Acts as a sequence specific DNA binding transcriptional activator or repressor.
CCNT2	Cyclin-T2	Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin T) complex, also called positive transcription elongation factor B (P-TEFB), which is proposed to facilitate the transition from abortive to production elongation by phosp…
APLN	Apelin	Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in cadiovascular homeostasis.
REC8	Meiotic recombination protein REC8 homolog	Required during meiosis for separation of sister chromatids and homologous chromosomes.
CDC7	Cell division cycle 7-related protein kinase	Kinase involved in initiation of DNA replication.
NEK9	Serine/threonine-protein kinase Nek9	Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation.
DDI1	Protein DDI1 homolog 1	Probable aspartic protease.
CKB	Creatine kinase B-type	Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate).
GREM1	Gremlin-1	Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop.
FANCL	E3 ubiquitin-protein ligase FANCL	Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway.
CROCC	Rootletin	Major structural component of the ciliary rootlet, a cytoskeletal-like structure in ciliated cells which originates from the basal body at the proximal end of a cilium and extends proximally toward the cell nucleus.
MCM9	DNA helicase MCM9	Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).
ERCC6L2	DNA excision repair protein ERCC-6-like 2	Promotes double-strand break (DSB) end-joining and facilitates programmed recombination by controlling how DNA ends are joined in a spatially oriented manner during repair.
HROB	Homologous recombination OB-fold protein	DNA-binding protein involved in homologous recombination that acts by recruiting the MCM8-MCM9 helicase complex to sites of DNA damage to promote DNA repair synthesis.
CAMSAP2	Calmodulin-regulated spectrin-associated protein 2	Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization.
USP53	Ubiquitin carboxyl-terminal hydrolase 53	Deubiquitinase that mediates ‘Lys-63’-linked deubiquitination of tight junction proteins, such as MARVELD2 and LSR, and which is involved in the survival of auditory hair cells and hearing.
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.
TOP1MT	DNA topoisomerase I, mitochondrial	Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex.
NUP107	Nuclear pore complex protein Nup107	Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance.
PREPL	Prolyl endopeptidase-like	Serine peptidase whose precise substrate specificity remains unclear.
UBR4	E3 ubiquitin-protein ligase UBR4	E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm.
SSH1	Protein phosphatase Slingshot homolog 1	Protein phosphatase which regulates actin filament dynamics.
CLPB	Mitochondrial disaggregase	Functions as a regulatory ATPase and participates in secretion/protein trafficking process.
EIF2B2	Translation initiation factor eIF2B subunit beta	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
ERCC1	DNA excision repair protein ERCC-1	Non-catalytic component of a structure-specific DNA repair endonuclease responsible for the 5’-incision during DNA repair.
ESRRB	Steroid hormone receptor ERR2	Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity.
ESRRG	Estrogen-related receptor gamma	Orphan receptor that acts as a transcription activator in the absence of bound ligand.
CENPI	Centromere protein I	Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation.
GGPS1	Geranylgeranyl pyrophosphate synthase	Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
AMHR2	Anti-Muellerian hormone type-2 receptor	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
HERC1	Probable E3 ubiquitin-protein ligase HERC1	Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin.
FOXK2	Forkhead box protein K2	Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis and autophagy.
MRE11	Double-strand break repair protein MRE11	Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
MSH4	MutS protein homolog 4	Involved in meiotic recombination.
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
NTRK3	NT-3 growth factor receptor	Receptor tyrosine kinase involved in nervous system and probably heart development.
NUP155	Nuclear pore complex protein Nup155	Essential component of nuclear pore complex.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.
RAD50	DNA repair protein RAD50	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
RAD51C	DNA repair protein RAD51 homolog 3	Essential for the homologous recombination (HR) pathway of DNA repair.

Protein-family classification

Druggable: 16 · Difficult: 7 · Unknown: 28 · Druggable fraction: 0.31

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
Nuclear receptor	2	15.1×	0.039
Kinase	6	3.3×	0.039
Protease	3	2.1×	0.433
Phosphatase	1	1.6×	0.802
Other/Unknown	28	1.0×	0.802
Enzyme (other)	4	0.9×	0.802
Transcription factor	5	0.8×	0.802
Scaffold/PPI	2	0.7×	0.802

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMPR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
SOX3	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
STAG1	Other/Unknown	no		STAG, ARM-type_fold, SCD
STAG3	Other/Unknown	no		STAG, ARM-type_fold, SCD
TFAM	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, HMGB
NEK8	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS
POF1B	Other/Unknown	no		POF1B, POF1B_HlH
PMEPA1	Other/Unknown	no		TMEPAI/LRAD4
MRPS7	Other/Unknown	no		Ribosomal_uS7, Ribosomal_uS7_dom, Ribosomal_uS7_dom_sf
TP63	Transcription factor	no		SAM, p53_tumour_suppressor, p53-like_TF_DNA-bd_sf
CCNT2	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, Cyclin-like_sf
APLN	Other/Unknown	no		Apelin
REC8	Other/Unknown	no		Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C
CDC7	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
NEK9	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS
DDI1	Protease	yes		Ubiquitin-like_dom, Peptidase_aspartic_DDI1-type, Peptidase_aspartic_dom_sf
CKB	Enzyme (other)	yes	2.7.3.2	ATP-guanido_PTrfase, Gln_synth/guanido_kin_cat_dom, ATP-guanido_PTrfase_N
GREM1	Other/Unknown	no		DAN_dom, Cys_knot_C, Gremlin-1/2
FANCL	Transcription factor	no	2.3.2.27	Znf_RING/FYVE/PHD, UBQ-conjugating_enzyme/RWD, FancL_WD-rpt_cont_dom
CROCC	Other/Unknown	no		Rootletin-like_CC
MCM9	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
TTC16	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt
ERCC6L2	Other/Unknown	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
HROB	Other/Unknown	no		HROB, HROB_OB
CAMSAP2	Other/Unknown	no		CH_dom, PRC_barrel-like_sf, CKK_CAMSAP
USP53	Protease	yes		Peptidase_C19_UCH, USP, Papain-like_cys_pep_sf
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4
TOP1MT	Enzyme (other)	yes	5.6.2.1	TopoI, TopoI_DNA-bd_euk, DNA_brk_join_enz
NUP107	Other/Unknown	no		Nup84/Nup107
PREPL	Protease	yes	3.4.21.26	Peptidase_S9_cat, Peptidase_S9A, Pept_S9A_N
UBR4	Transcription factor	no		Znf_UBR, ARM-type_fold, E3_Ub_ligase_UBR4_C
SSH1	Phosphatase	yes		Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, DEK_C
CLPB	Scaffold/PPI	no		ClpA/B, Ankyrin_rpt, AAA+_ATPase
EIF2B2	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, IF_2B-like_C
ERCC1	Other/Unknown	no		ERCC1/RAD10/SWI10, RuvA_2-like, Restrct_endonuc-II-like
ESRRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
ESRRG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
CENPI	Other/Unknown	no		CENP-I
TH2LCRR	Other/Unknown	no
GGPS1	Enzyme (other)	yes	2.5.1.29	Polyprenyl_synt, Isoprenoid_synthase_dom_sf, Polyprenyl_synt_CS
AMHR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Kinase-like_dom_sf
HERC1	Scaffold/PPI	no		Reg_chr_condens, HECT_dom, WD40_rpt
FOXK2	Transcription factor	no		FHA_dom, Fork_head_dom, SMAD_FHA_dom_sf
MRE11	Other/Unknown	no		Mre11, Calcineurin-like_PHP, Mre11_DNA-bd
MSH4	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS_core, DNA_mmatch_repair_MutS_con_dom
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
NTRK3	Kinase	yes	2.7.10.1	LRRNT, Cys-rich_flank_reg_C, Prot_kinase_dom
NUP155	Other/Unknown	no		Nucleoporin_Nup155, Nucleoporin_Nup133/Nup155_C, Nucleoporin_Nup133/Nup155_N
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
RAD50	Other/Unknown	no		Rad50_eukaryotes, Zn_hook_RAD50, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	51
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	7
right testis	7
left testis	6
secondary oocyte	6
sural nerve	5
oocyte	5
right uterine tube	5
sperm	5
male germ line stem cell (sensu Vertebrata) in testis	5
bronchial epithelial cell	4
endothelial cell	4
Brodmann (1909) area 23	4
ventricular zone	3
cauda epididymis	2
ganglionic eminence	2
parotid gland	2
left lobe of thyroid gland	2
metanephros cortex	2
skin of abdomen	2
skin of leg	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMPR1B	239	broad	marker	calcaneal tendon, bronchial epithelial cell, cauda epididymis
SOX3	72	broad	marker	ventricular zone, ganglionic eminence, embryo
STAG1	293	ubiquitous	marker	calcaneal tendon, parotid gland, sural nerve
STAG3	185	broad	marker	oocyte, right testis, left testis
TFAM	284	ubiquitous	marker	right testis, left testis, secondary oocyte
NEK8	196	ubiquitous	marker	buccal mucosa cell, metanephros cortex, left lobe of thyroid gland
POF1B	176	broad	marker	upper arm skin, skin of leg, skin of abdomen
PMEPA1	277	ubiquitous	marker	visceral pleura, ascending aorta, thoracic aorta
MRPS7	289	ubiquitous	marker	gastrocnemius, apex of heart, heart left ventricle
TP63	207	broad	marker	upper leg skin, skin of hip, upper arm skin
CCNT2	295	ubiquitous	marker	adrenal tissue, calcaneal tendon, body of pancreas
APLN	177	broad	yes	C1 segment of cervical spinal cord, spinal cord, left ventricle myocardium
REC8	134	broad	marker	adenohypophysis, pituitary gland, ganglionic eminence
CDC7	218	ubiquitous	marker	secondary oocyte, oocyte, endothelial cell
NEK9	296	ubiquitous	marker	tibia, right uterine tube, left ovary
DDI1	23	tissue_specific	yes	sperm, left testis, right testis
CKB	284	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GREM1	126	ubiquitous	marker	stromal cell of endometrium, gall bladder, mucosa of stomach
FANCL	293	ubiquitous	marker	pituitary gland, adenohypophysis, calcaneal tendon
CROCC	222	broad	marker	right uterine tube, sural nerve, right hemisphere of cerebellum
MCM9	233	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis
TTC16	119	tissue_specific	marker	right uterine tube, bronchial epithelial cell, granulocyte
ERCC6L2	255	ubiquitous	marker	epithelial cell of pancreas, Brodmann (1909) area 23, endothelial cell
HROB	162	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, type B pancreatic cell, diaphragm
CAMSAP2	291	ubiquitous	marker	lateral nuclear group of thalamus, postcentral gyrus, parietal lobe
USP53	269	ubiquitous	marker	calcaneal tendon, tibial nerve, mucosa of stomach
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
TOP1MT	203	ubiquitous	marker	right lobe of liver, sural nerve, left ovary
NUP107	283	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
PREPL	294	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPS7	5,544
CLPB	5,095
TFAM	4,690
NTRK3	4,147
CENPI	4,030
MRE11	3,932
NUP155	3,663
NUP107	3,524
RAD51C	3,396
CDC7	2,963

Intra-cohort edges

A	B	Sources
CLPB	REC8	biogrid_interaction
ESRRB	ESRRG	intact
FANCL	RAD51C	string_interaction
FOXK2	TP63	biogrid_interaction, intact
FOXK2	UBR4	intact
HROB	MCM9	string_interaction
MCM9	STAG3	string_interaction
MRE11	NBN	intact, string_interaction
MRE11	RAD50	biogrid_interaction, intact, string_interaction
MRE11	RAD51C	string_interaction
NBN	RAD50	biogrid_interaction, intact, string_interaction
NEK8	NEK9	biogrid_interaction
NUP107	NUP155	string_interaction
REC8	STAG1	string_interaction
REC8	STAG3	string_interaction

Structural data

PDB: 37 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS7	Q9Y2R9	77
ESRRG	P62508	43
EIF2B2	P49770	27
TP63	Q9H3D4	26
STAG1	Q8WVM7	20
RAD51C	O43502	17
TFAM	Q00059	16
ERCC1	P07992	14
UBR4	Q5T4S7	13
CENPI	Q92674	12
MRE11	P49959	10
NUP155	O75694	10
CDC7	O00311	9
GGPS1	O95749	9
FANCL	Q9NW38	8
NUP107	P57740	7
CLPB	Q9H078	7
NBN	O60934	7
CKB	P12277	6
MCM9	Q9NXL9	6
RAD50	Q92878	6
APLN	Q9ULZ1	5
NTRK3	Q16288	5
ESRRB	O95718	3
NEK9	Q8TD19	2
GREM1	O60565	2
CROCC	Q5TZA2	2
ERCC6L2	Q5T890	2
DNAH1	Q9P2D7	2
PREPL	Q4J6C6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TOP1MT	Q969P6	91.07
NEK8	Q86SG6	85.23
STAG3	Q9UJ98	78.46
MSH4	O15457	75.12
PEX6	Q13608	69.87
TTC16	Q8NEE8	65.70
REC8	O95072	65.16
SOX3	P41225	58.40
CAMSAP2	Q08AD1	57.60
PMEPA1	Q969W9	57.03
SSH1	Q8WYL5	55.41
USP53	Q70EK8	55.34
HROB	Q8N3J3	55.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 206. Enrichment computed across 51 evidence-associated genes (35 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 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Meiosis	5	40.8×	3e-05	STAG1, STAG3, MRE11, MSH4, NBN
Sensing of DNA Double Strand Breaks	3	163.1×	4e-05	MRE11, NBN, RAD50
Impaired BRCA2 binding to PALB2	4	52.2×	4e-05	MRE11, NBN, RAD50, RAD51C
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	4	48.3×	4e-05	MRE11, NBN, RAD50, RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	4	48.3×	4e-05	MRE11, NBN, RAD50, RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	4	48.3×	4e-05	MRE11, NBN, RAD50, RAD51C
Reproduction	5	27.2×	4e-05	STAG1, STAG3, MRE11, MSH4, NBN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	4	45.0×	4e-05	MRE11, NBN, RAD50, RAD51C
Homologous DNA Pairing and Strand Exchange	4	43.5×	4e-05	MRE11, NBN, RAD50, RAD51C
Cell Cycle	8	8.2×	8e-05	STAG1, STAG3, CDC7, NEK9, CENPI, MRE11, MSH4, NBN
Resolution of D-loop Structures through Holliday Junction Intermediates	4	34.4×	9e-05	MRE11, NBN, RAD50, RAD51C
HDR through Single Strand Annealing (SSA)	4	33.5×	1e-04	ERCC1, MRE11, NBN, RAD50
Meiotic recombination	5	18.5×	1e-04	MRE11, MSH4, NBN, RAD50, RAD51C
HDR through MMEJ (alt-NHEJ)	3	75.3×	1e-04	MRE11, NBN, RAD50
Presynaptic phase of homologous DNA pairing and strand exchange	4	31.1×	1e-04	MRE11, NBN, RAD50, RAD51C
HDR through Homologous Recombination (HRR)	4	21.8×	4e-04	MRE11, NBN, RAD50, RAD51C
Nuclear Pore Complex (NPC) Disassembly	3	26.5×	0.002	NEK9, NUP107, NUP155
Impaired BRCA2 binding to RAD51	3	26.5×	0.002	MRE11, NBN, RAD50
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2	54.4×	0.006	MRE11, NBN
Cell Cycle Checkpoints	4	10.1×	0.006	CDC7, CENPI, MRE11, NBN
Diseases of DNA Double-Strand Break Repair	2	46.6×	0.008	MRE11, NBN
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2	46.6×	0.008	MRE11, NBN
Nonhomologous End-Joining (NHEJ)	3	14.4×	0.010	MRE11, NBN, RAD50
DNA Damage/Telomere Stress Induced Senescence	3	14.0×	0.011	MRE11, NBN, RAD50
Resolution of D-Loop Structures	2	36.2×	0.011	MRE11, NBN
Diseases of DNA repair	2	32.6×	0.012	MRE11, NBN
SUMOylation of DNA damage response and repair proteins	3	12.6×	0.012	STAG1, NUP107, NUP155
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	3	12.6×	0.012	MRE11, NBN, RAD50
Mitotic Prometaphase	4	7.9×	0.012	STAG1, NEK9, NUP107, CENPI
Meiotic synapsis	3	12.1×	0.013	STAG1, STAG3, REC8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 49 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sister chromatid cohesion	5	78.2×	2e-06	STAG1, STAG3, REC8, MRE11, RAD51C
reciprocal meiotic recombination	5	57.3×	5e-06	REC8, MRE11, MSH4, RAD50, RAD51C
telomeric 3’ overhang formation	3	257.9×	1e-05	MRE11, NBN, RAD50
double-strand break repair via homologous recombination	6	19.1×	7e-05	REC8, MCM9, MRE11, NBN, RAD50, RAD51C
DNA strand resection involved in replication fork processing	3	129.0×	1e-04	MRE11, NBN, RAD50
R-loop processing	3	103.2×	2e-04	MRE11, NBN, RAD50
DNA double-strand break processing	3	93.8×	2e-04	MRE11, NBN, RAD50
homologous recombination	3	86.0×	2e-04	MRE11, NBN, RAD50
interstrand cross-link repair	4	35.3×	2e-04	FANCL, ERCC6L2, HROB, ERCC1
regulation of mitotic recombination	2	343.9×	4e-04	MRE11, RAD50
female gamete generation	3	49.1×	0.001	MCM9, HROB, MSH4
mitotic G2/M transition checkpoint	3	49.1×	0.001	MRE11, NBN, RAD50
DNA damage response	7	7.6×	0.001	TP63, FANCL, MCM9, ERCC6L2, HROB, MRE11, RAD50
negative regulation of telomere capping	2	137.6×	0.003	NBN, RAD50
double-strand break repair	4	16.6×	0.003	REC8, MRE11, NBN, RAD50
positive regulation of telomere maintenance	3	31.3×	0.003	MRE11, NBN, RAD50
positive regulation of double-strand break repair	3	21.1×	0.010	MRE11, NBN, RAD50
DNA recombination	3	20.6×	0.010	MRE11, RAD50, RAD51C
telomere maintenance via recombination	2	62.5×	0.010	RAD50, RAD51C
t-circle formation	2	57.3×	0.012	ERCC1, NBN
telomere maintenance	3	16.4×	0.017	MRE11, NBN, RAD50
DNA repair	5	6.5×	0.019	FANCL, ERCC1, MRE11, RAD50, RAD51C
sex differentiation	2	34.4×	0.027	CENPI, AMHR2
isotype switching	2	34.4×	0.027	ERCC1, NBN
female gonad development	2	32.8×	0.029	NUP107, AMHR2
telomere maintenance via telomerase	2	29.9×	0.033	MRE11, RAD50
meiotic DNA recombinase assembly	1	343.9×	0.034	RAD51C
female meiosis sister chromatid cohesion	1	343.9×	0.034	RAD51C
ectoderm and mesoderm interaction	1	343.9×	0.034	TP63
epidermal cell division	1	343.9×	0.034	TP63

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 10 · Undrugged: 41

Druggability breadth: 22 of 51 evidence-associated genes (43%) 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
BMPR1B	MOMELOTINIB
CCNT2	PALBOCICLIB
NEK9	MOMELOTINIB
ESRRB	ESTRADIOL
ESRRG	DIETHYLSTILBESTROL
GGPS1	MINODRONIC ACID
NTRK3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NTRK3	41	4
BMPR1B	28	4
NEK9	21	4
CDC7	7	2
GGPS1	4	4
CCNT2	3	4
ESRRB	2	4
ESRRG	2	4
NUP155	1	2
RAD50	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1B, NEK9
FEDRATINIB	4	BMPR1B, NEK9, NTRK3
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B, NTRK3
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B, NTRK3
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B, NTRK3
CRIZOTINIB	4	BMPR1B, NEK9, NTRK3
PALBOCICLIB	4	CCNT2
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
ESTRADIOL	4	ESRRB
DIETHYLSTILBESTROL	4	ESRRG
TAMOXIFEN	4	ESRRG
MINODRONIC ACID	4	GGPS1
ZOLEDRONIC ACID	4	GGPS1
IBANDRONIC ACID	4	GGPS1
SORAFENIB	4	NTRK3
ENTRECTINIB	4	NTRK3
NILOTINIB	4	NTRK3
BOSUTINIB	4	NTRK3
LORLATINIB	4	NTRK3
PEXIDARTINIB	4	NTRK3
LAROTRECTINIB	4	NTRK3
LAROTRECTINIB SULFATE	4	NTRK3
REPOTRECTINIB	4	NTRK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
NTRK3	408	Binding:400, Functional:4, ADMET:4
NEK9	254	Binding:254
CDC7	222	Binding:221, Functional:1
BMPR1B	166	Binding:164, ADMET:2
ESRRG	135	Binding:121, Functional:13, ADMET:1
GGPS1	129	Binding:128, ADMET:1
NEK8	37	Binding:37
MRE11	36	Binding:36
ERCC1	28	Binding:28
ESRRB	27	Binding:19, Functional:8
CCNT2	16	Binding:16
UBR4	11	Binding:11
NUP155	9	Binding:9
RAD50	7	Binding:7
MRPS7	3	Binding:3
CKB	2	Binding:2
NBN	2	Binding:2
TFAM	1	Binding:1
POF1B	1	Binding:1
CROCC	1	Binding:1
PREPL	1	Binding:1
EIF2B2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1B	2.7.10.2	non-specific protein-tyrosine kinase
CDC7	2.7.11.1	non-specific serine/threonine protein kinase
CKB	2.7.3.2	creatine kinase
FANCL	2.3.2.27	RING-type E3 ubiquitin transferase
TOP1MT	5.6.2.1	DNA topoisomerase
PREPL	3.4.21.26	prolyl oligopeptidase
GGPS1	2.5.1.29	geranylgeranyl diphosphate synthase
AMHR2	2.7.10.2	non-specific protein-tyrosine kinase
NTRK3	2.7.10.1	receptor protein-tyrosine kinase
PEX6	3.6.4.7	peroxisome-assembly ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR1B	166
CDC7	222
NEK9	254
ESRRG	135
GGPS1	129
NTRK3	408

Pharmacogenomics

Cohort genes with a PharmGKB record: 49; 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	BMPR1B, NEK9
FEDRATINIB	4	BMPR1B, NEK9, NTRK3
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B, NTRK3
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B, NTRK3
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B, NTRK3
CRIZOTINIB	4	BMPR1B, NEK9, NTRK3
PALBOCICLIB	4	CCNT2
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
DIETHYLSTILBESTROL	4	ESRRG
TAMOXIFEN	4	ESRRG
MINODRONIC ACID	4	GGPS1
ZOLEDRONIC ACID	4	GGPS1
IBANDRONIC ACID	4	GGPS1
SORAFENIB	4	NTRK3
ENTRECTINIB	4	NTRK3
NILOTINIB	4	NTRK3
BOSUTINIB	4	NTRK3
LORLATINIB	4	NTRK3
PEXIDARTINIB	4	NTRK3
LAROTRECTINIB	4	NTRK3
LAROTRECTINIB SULFATE	4	NTRK3
REPOTRECTINIB	4	NTRK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	BMPR1B, CCNT2, NEK9, ESRRB, ESRRG, GGPS1, NTRK3
B	Phased (≥1) drug, not yet approved	3	CDC7, NUP155, RAD50
C	Druggable family + PDB, no drug	4	DDI1, CKB, PREPL, AMHR2
D	Druggable family + AlphaFold only, no drug	5	NEK8, USP53, TOP1MT, SSH1, PEX6
E	Difficult family or no structure, no drug	32	SOX3, STAG1, STAG3, TFAM, POF1B, PMEPA1, MRPS7, TP63, APLN, REC8 (+22 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MRE11	36	RAD50
NBN	2	RAD50
SOX3	0	—
STAG1	0	—
STAG3	0	—
TFAM	1	—
NEK8	37	—
POF1B	1	—
PMEPA1	0	—
MRPS7	3	—
TP63	0	—
APLN	0	—
REC8	0	—
DDI1	0	—
CKB	2	—
GREM1	0	—
FANCL	0	—
CROCC	1	—
MCM9	0	—
TTC16	0	—
ERCC6L2	0	—
HROB	0	—
CAMSAP2	0	—
USP53	0	—
DNAH1	0	—
TOP1MT	0	—
NUP107	0	—
PREPL	1	—
UBR4	11	—
SSH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 82.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	46
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
NITRIC ACID	3	1
ORGANON	2	2
SOLIZMESTROCEL	2	1
CHEMBL1078369	0	1
CHEMBL31399	0	1
CHEMBL287148	0	1
CHEMBL2370644	0	1
CHEMBL186200	0	1