Amenorrhea

Summary

Amenorrhea (MONDO:0001836) is a disease with 41 cohort genes (11 GWAS associations across 2 studies) and 34 clinical trials. The dominant Reactome pathway is Hormone ligand-binding receptors (3 cohort genes). Top therapeutic interventions include estradiol, estrogens, conjugated, and ethinyl estradiol.

At a glance

• Cohort genes: 41
• GWAS associations: 11
• ClinVar variants: 53
• Clinical trials: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amenorrhea
Mondo ID	MONDO:0001836
MeSH	D000568
DOID	DOID:13938
NCIT	C61443
UMLS	C0002453
MedGen	8016
Is cancer (heuristic)	no

Also known as: absence of menstruation · amenorrhea · amenorrhea (disease)

Data availability: 53 ClinVar variants · 11 GWAS associations (2 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › female reproductive system disorder › menstrual disorder › amenorrhea

Related subtypes (2): premenstrual tension, dysmenorrhea

Subtypes (3): calloso-genital dysplasia, primary amenorrhea, secondary amenorrhea

Genetics & variants

GWAS landscape

11 GWAS associations across 2 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs147451859	6e-09	PPCDC	G	1.74
rs11031002	1e-08	ARL14EP-DT	T	0.87
rs17587029	3e-08	CHCHD5 - SLC20A1-DT	G	1.84
rs6488809	3e-07	DERA	T	1.74
rs1410669	5e-07	RNU4-66P - RIMS1	G	1.71
rs11096688	7e-07	LINC02850 - APOB	T	1.45
rs73419340	8e-07	VPS50 - CALCR	A	0.49
rs1189020	9e-07	LINC02284	T	1.61
rs1119997	1e-06	ADCY8 - IADEN	G	1.3
rs78264913	1e-06	TMTC1	C	1.53
rs77569618	1e-06	LINC02236	A	1.48

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90454219	Pujol Gualdo N	2025	8,884	214,040	Atlas of genetic and phenotypic associations across 42 female reproductive health diagnoses.
GCST009153	Ruddy KJ	2019	457	0	Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

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	1
Tier 4: intronic/intergenic	10

MAF distribution

Bucket	Variants
common (>=0.05)	11
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	8
intergenic_variant	2
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs147451859	15	75039102	C>G	0.07	intron_variant	PPCDC	6e-09	Tier 4: intronic/intergenic
rs11031002	11	30193714	T>A	0.05	intron_variant	ARL14EP-DT	1e-08	Tier 4: intronic/intergenic
rs17587029	2	112624477	A>C,G,T	0.05	regulatory_region_variant	CHCHD5 - SLC20A1-DT	3e-08	Tier 3: regulatory
rs6488809	12	16001304	G>T	0.06	intron_variant	DERA	3e-07	Tier 4: intronic/intergenic
rs1410669	6	71740732	G>A,T	0.07	intron_variant	RNU4-66P - RIMS1	5e-07	Tier 4: intronic/intergenic
rs11096688	2	20885650	T>A,C,G	0.1	intergenic_variant	LINC02850 - APOB	7e-07	Tier 4: intronic/intergenic
rs73419340	7	93388705	G>A	0.06	intergenic_variant	VPS50 - CALCR	8e-07	Tier 4: intronic/intergenic
rs1189020	14	56410241	T>A,C,G	0.06	intron_variant	LINC02284	9e-07	Tier 4: intronic/intergenic
rs1119997	8	131109670	A>C,G,T	0.46	intron_variant	ADCY8 - IADEN	1e-06	Tier 4: intronic/intergenic
rs78264913	12	29733920	T>C	0.05	intron_variant	TMTC1	1e-06	Tier 4: intronic/intergenic
rs77569618	5	6784082	T>A,C,G	0.09	intron_variant	LINC02236	1e-06	Tier 4: intronic/intergenic

ClinVar germline variants

53 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 16 conflicting classifications of pathogenicity, 3 likely benign, 3 benign/likely benign, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523337	NM_000145.4(FSHR):c.2T>C (p.Met1Thr)	FSHR	Pathogenic	criteria provided, single submitter
16024	NM_000406.3(GNRHR):c.785G>A (p.Arg262Gln)	GNRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16028	NM_000406.3(GNRHR):c.504T>A (p.Ser168Arg)	GNRHR	Pathogenic	criteria provided, multiple submitters, no conflicts
224350	NM_000216.4(ANOS1):c.2015A>G (p.His672Arg)	ANOS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
529141	NM_017780.4(CHD7):c.5824C>T (p.Arg1942Trp)	CHD7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581160	NM_017780.4(CHD7):c.1375C>T (p.Arg459Cys)	CHD7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
588393	NM_017780.4(CHD7):c.2182G>C (p.Asp728His)	CHD7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
187790	NM_005215.4(DCC):c.1409G>A (p.Gly470Asp)	DCC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267733	NM_003865.3(HESX1):c.385G>A (p.Val129Ile)	HESX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344745	NM_001366057.1(OTUD4):c.2993C>G (p.Pro998Arg)	OTUD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254737	NM_018082.6(POLR3B):c.2161A>T (p.Lys721Ter)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285205	NM_018082.6(POLR3B):c.1244T>C (p.Met415Thr)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3451	NM_144773.4(PROKR2):c.254G>A (p.Arg85His)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633661	NM_144773.4(PROKR2):c.332T>G (p.Met111Arg)	PROKR2	Conflicting classifications of pathogenicity	no assertion criteria provided
196432	NM_006261.5(PROP1):c.425C>T (p.Ala142Val)	PROP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
705733	NM_012414.4(RAB3GAP2):c.3616G>T (p.Asp1206Tyr)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68836	NM_006080.3(SEMA3A):c.458A>G (p.Asn153Ser)	SEMA3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167717	NC_000003.12:g.181712424G>A	SOX2-OT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50874	NM_001127496.3(SPRY4):c.653C>A (p.Ser218Tyr)	SPRY4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344766	NM_000216.4(ANOS1):c.1111G>A (p.Val371Ile)	ANOS1	Uncertain significance	no assertion criteria provided
1344764	NM_021913.5(AXL):c.874del (p.His292fs)	AXL	Uncertain significance	no assertion criteria provided
1344753	NM_017780.4(CHD7):c.5114C>A (p.Pro1705Gln)	CHD7	Uncertain significance	no assertion criteria provided
1344762	NM_005215.4(DCC):c.2455G>A (p.Asp819Asn)	DCC	Uncertain significance	no assertion criteria provided
1344763	NM_005215.4(DCC):c.2647G>A (p.Val883Ile)	DCC	Uncertain significance	no assertion criteria provided
1344760	NM_001378457.1(DMXL2):c.1687A>G (p.Met563Val)	DMXL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1344761	NM_001378457.1(DMXL2):c.1427C>G (p.Thr476Ser)	DMXL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1344750	NM_023110.3(FGFR1):c.779G>A (p.Gly260Glu)	FGFR1	Uncertain significance	no assertion criteria provided
1344765	NM_198391.3(FLRT3):c.1202A>T (p.Gln401Leu)	FLRT3	Uncertain significance	no assertion criteria provided
523336	NM_000145.4(FSHR):c.153-11T>A	FSHR	Uncertain significance	criteria provided, single submitter
1344749	NM_001083111.2(GNRH1):c.143T>G (p.Ile48Arg)	GNRH1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 76 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome
SEMA3E	Orphanet:138	CHARGE syndrome
TACR3	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
TACR3	Orphanet:478	Kallmann syndrome
WDR11	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
WDR11	Orphanet:478	Kallmann syndrome
WDR11	Orphanet:95496	Pituitary stalk interruption syndrome
SPRY4	Orphanet:363494	Non-seminomatous germ cell tumor of testis
SPRY4	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
SPRY4	Orphanet:478	Kallmann syndrome
PHIP	Orphanet:589905	PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome
PROKR2	Orphanet:3157	Septo-optic dysplasia spectrum
PROKR2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROKR2	Orphanet:478	Kallmann syndrome
PROKR2	Orphanet:95496	Pituitary stalk interruption syndrome
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
RAB3GAP1	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP1	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69
RIMS1	Orphanet:1872	Cone rod dystrophy
PROK2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROK2	Orphanet:478	Kallmann syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
FEZF1	Orphanet:478	Kallmann syndrome
DCC	Orphanet:238722	Familial congenital mirror movements
DCC	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
DCC	Orphanet:478	Kallmann syndrome
DMXL2	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
DMXL2	Orphanet:453533	Polyendocrine-polyneuropathy syndrome
DMXL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
POLR3B	Orphanet:85186	Endosteal sclerosis-cerebellar hypoplasia syndrome
POLR3B	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia

Cohort genes → proteins

41 cohort genes, 39 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	10
multi_evidence	31

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	clinvar
SEMA3E	HGNC:10727	ENSG00000170381	O15041	Semaphorin-3E	clinvar
SRA1	HGNC:11281	ENSG00000213523	Q9HD15	Steroid receptor RNA activator 1	clinvar
TACR3	HGNC:11528	ENSG00000169836	P29371	Neuromedin-K receptor	clinvar
WDR11	HGNC:13831	ENSG00000120008	Q9BZH6	WD repeat-containing protein 11	clinvar
KLB	HGNC:15527	ENSG00000134962	Q86Z14	Beta-klotho	clinvar
SPRY4	HGNC:15533	ENSG00000187678	Q9C004	Protein sprouty homolog 4	clinvar
PHIP	HGNC:15673	ENSG00000146247	Q8WWQ0	PH-interacting protein	clinvar
PROKR2	HGNC:15836	ENSG00000101292	Q8NFJ6	Prokineticin receptor 2	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
TENT4A	HGNC:16705	ENSG00000112941	Q5XG87	Terminal nucleotidyltransferase 4A	gwas
RAB3GAP1	HGNC:17063	ENSG00000115839	Q15042	Rab3 GTPase-activating protein catalytic subunit	clinvar
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	clinvar
RIMS1	HGNC:17282	ENSG00000079841	Q86UR5	Regulating synaptic membrane exocytosis protein 1	gwas
PROK2	HGNC:18455	ENSG00000163421	Q9HC23	Prokineticin-2	clinvar
SOX2-OT	HGNC:20209	ENSG00000242808		SOX2 overlapping transcript	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
FEZF1	HGNC:22788	ENSG00000128610	A0PJY2	Fez family zinc finger protein 1	clinvar
ADCY8	HGNC:239	ENSG00000155897	P40145	Adenylate cyclase type 8	gwas
TMTC1	HGNC:24099	ENSG00000133687	Q8IUR5	Protein O-mannosyl-transferase TMTC1	gwas
DERA	HGNC:24269	ENSG00000023697	Q9Y315	Deoxyribose-phosphate aldolase	gwas
OTUD4	HGNC:24949	ENSG00000164164	Q01804	OTU domain-containing protein 4	clinvar
VPS50	HGNC:25956	ENSG00000004766	Q96JG6	Syndetin	gwas
LDAH	HGNC:26145	ENSG00000118961	Q9H6V9	Lipid droplet-associated hydrolase	gwas
DCC	HGNC:2701	ENSG00000187323	P43146	Netrin receptor DCC	clinvar
PPCDC	HGNC:28107	ENSG00000138621	Q96CD2	Phosphopantothenoylcysteine decarboxylase	gwas
DMXL2	HGNC:2938	ENSG00000104093	Q8TDJ6	DmX-like protein 2	clinvar
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	clinvar
RPS20P11	HGNC:36084			ribosomal protein S20 pseudogene 11	gwas
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
FLRT3	HGNC:3762	ENSG00000125848	Q9NZU0	Leucine-rich repeat transmembrane protein FLRT3	clinvar
FSHR	HGNC:3969	ENSG00000170820	P23945	Follicle-stimulating hormone receptor	clinvar
GNRH1	HGNC:4419	ENSG00000147437	P01148	Progonadoliberin-1	clinvar
GNRHR	HGNC:4421	ENSG00000109163	P30968	Gonadotropin-releasing hormone receptor	clinvar
HESX1	HGNC:4877	ENSG00000163666	Q9UBX0	Homeobox expressed in ES cells 1	clinvar
ANOS1	HGNC:6211	ENSG00000011201	P23352	Anosmin-1	clinvar
KL	HGNC:6344	ENSG00000133116	Q9UEF7	Klotho	clinvar
LHX3	HGNC:6595	ENSG00000107187	Q9UBR4	LIM/homeobox protein Lhx3	clinvar
PELI2	HGNC:8828	ENSG00000139946	Q9HAT8	E3 ubiquitin-protein ligase pellino homolog 2	gwas
AXL	HGNC:905	ENSG00000167601	P30530	Tyrosine-protein kinase receptor UFO	clinvar
PROP1	HGNC:9455	ENSG00000175325	O75360	Homeobox protein prophet of Pit-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.
SEMA3E	Semaphorin-3E	Plays an important role in signaling via the cell surface receptor PLXND1.
SRA1	Steroid receptor RNA activator 1	Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors.
TACR3	Neuromedin-K receptor	Receptor for the tachykinin neuromedin-K (neurokinin B), also able to bind and respond to tachynins substance K/neurokinin A and substance P.
WDR11	WD repeat-containing protein 11	Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis.
KLB	Beta-klotho	Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.
SPRY4	Protein sprouty homolog 4	Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras.
PHIP	PH-interacting protein	Probable regulator of the insulin and insulin-like growth factor signaling pathways.
PROKR2	Prokineticin receptor 2	Receptor for prokineticin 2.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
TENT4A	Terminal nucleotidyltransferase 4A	Terminal nucleotidyltransferase that catalyzes preferentially the transfer of ATP and GTP on RNA 3’ poly(A) tail creating a heterogeneous 3’ poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation.
RAB3GAP1	Rab3 GTPase-activating protein catalytic subunit	Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
RIMS1	Regulating synaptic membrane exocytosis protein 1	Rab effector involved in exocytosis.
PROK2	Prokineticin-2	May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
FEZF1	Fez family zinc finger protein 1	Transcription repressor.
ADCY8	Adenylate cyclase type 8	Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion.
TMTC1	Protein O-mannosyl-transferase TMTC1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
DERA	Deoxyribose-phosphate aldolase	Catalyzes a reversible aldol reaction between acetaldehyde and D-glyceraldehyde 3-phosphate to generate 2-deoxy-D-ribose 5-phosphate.
OTUD4	OTU domain-containing protein 4	Deubiquitinase which hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein.
VPS50	Syndetin	Acts as a component of the EARP complex that is involved in endocytic recycling.
LDAH	Lipid droplet-associated hydrolase	Probable serine lipid hydrolase associated with lipid droplets.
DCC	Netrin receptor DCC	Receptor for netrin required for axon guidance.
PPCDC	Phosphopantothenoylcysteine decarboxylase	Catalyzes the decarboxylation of the cysteine moiety of 4-phosphopantothenoylcysteine to form 4’-phosphopantotheine and this reaction forms part of the biosynthesis of coenzyme A.
DMXL2	DmX-like protein 2	May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles.
POLR3B	DNA-directed RNA polymerase III subunit RPC2	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
FLRT3	Leucine-rich repeat transmembrane protein FLRT3	Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners.
FSHR	Follicle-stimulating hormone receptor	G protein-coupled receptor for follitropin, the follicle-stimulating hormone.
GNRH1	Progonadoliberin-1	Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
GNRHR	Gonadotropin-releasing hormone receptor	Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
HESX1	Homeobox expressed in ES cells 1	Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland.
ANOS1	Anosmin-1	Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex.
KL	Klotho	May have weak glycosidase activity towards glucuronylated steroids.
LHX3	LIM/homeobox protein Lhx3	Transcription factor.
PELI2	E3 ubiquitin-protein ligase pellino homolog 2	E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.
AXL	Tyrosine-protein kinase receptor UFO	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migratio…
PROP1	Homeobox protein prophet of Pit-1	Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Protein-family classification

Druggable: 14 · Difficult: 8 · Unknown: 19 · Druggable fraction: 0.34

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
Antibody/Immunoglobulin	5	3.6×	0.101
GPCR	4	2.3×	0.363
Kinase	2	1.4×	0.876
Scaffold/PPI	3	1.3×	0.876
Transcription factor	5	1.0×	0.904
Protease	1	0.9×	0.905
Other/Unknown	19	0.8×	0.916
Enzyme (other)	2	0.6×	0.916

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SEMA3E	Antibody/Immunoglobulin	yes		Semap_dom, Ig-like_dom, Immunoglobulin_dom
SRA1	Other/Unknown	no		SRA1/Sec31, Steroid_recept_RNA_1
TACR3	GPCR	yes		GPCR_Rhodpsn, NK3_rcpt, Neurokn_rcpt
WDR11	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
KLB	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf
SPRY4	Other/Unknown	no		Sprouty, Sprouty_domain
PHIP	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
PROKR2	GPCR	yes		GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
TENT4A	Enzyme (other)	yes	2.7.7.19	PAP_assoc, NT_sf, Trf4-like
RAB3GAP1	Other/Unknown	no		Rab3GAP1_conserved, Rab3GAP1_C, Rab3GAP1
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N
RIMS1	Transcription factor	no		C2_dom, PDZ, Rab_BD
PROK2	Other/Unknown	no		Prokineticin, Prokineticin_domain
SOX2-OT	Other/Unknown	no
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
FEZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
ADCY8	Other/Unknown	no		A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS
TMTC1	Other/Unknown	no		HAT, TPR-like_helical_dom_sf, TPR_2
DERA	Enzyme (other)	yes	4.1.2.4	DeoC/FbaB/LacD_aldolase, DeoC, Aldolase_TIM
OTUD4	Protease	yes		OTU_dom, Papain-like_cys_pep_sf, Peptidase_C85-like
VPS50	Other/Unknown	no		Syndetin_C, VPS54_N, VPS50
LDAH	Other/Unknown	no		LDAH, AB_hydrolase_fold
DCC	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PPCDC	Other/Unknown	no		Flavoprotein, Flavin_trans-like
DMXL2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, Rav1p_C
POLR3B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
RPS20P11	Other/Unknown	no
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FLRT3	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
FSHR	GPCR	yes		GPCR_Rhodpsn, LRRNT, Gphrmn_rcpt_fam
GNRH1	Other/Unknown	no		GnRH, Gonadoliberin_I_precursor, Gonadoliberin
GNRHR	GPCR	yes		GPCR_Rhodpsn, GphnRH_fam_rcpt, GPCR_Rhodpsn_7TM
HESX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ANOS1	Antibody/Immunoglobulin	yes		FN3_dom, WAP_dom, Ig-like_fold
KL	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf, GH_1_N_CS
LHX3	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
PELI2	Other/Unknown	no		Pellino_fam, Pellino_FHA, Pellino_RING
AXL	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub
PROP1	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 1.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	39
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
cortical plate	6
secondary oocyte	6
calcaneal tendon	4
stromal cell of endometrium	3
buccal mucosa cell	3
ventricular zone	3
lateral nuclear group of thalamus	3
endothelial cell	3
adenohypophysis	3
hypothalamus	2
granulocyte	2
hair follicle	2
choroid plexus epithelium	2
dorsal root ganglion	2
blood	2
nephron tubule	2
adrenal tissue	2
primordial germ cell in gonad	2
lower esophagus mucosa	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium
SEMA3E	197	broad	marker	cortical plate, calcaneal tendon, blood vessel layer
SRA1	254	ubiquitous	marker	pancreatic ductal cell, left adrenal gland, left adrenal gland cortex
TACR3	43	tissue_specific	marker	cortical plate, secondary oocyte, hypothalamus
WDR11	287	ubiquitous	marker	epithelium of nasopharynx, nasopharynx, calcaneal tendon
KLB	146	broad	marker	sperm, buccal mucosa cell, liver
SPRY4	219	ubiquitous	marker	left coronary artery, right lung, ascending aorta
PHIP	302	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, ventricular zone
PROKR2	32	tissue_specific	yes	cortical plate, ganglionic eminence, ventricular zone
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung
TENT4A	293	ubiquitous	marker	secondary oocyte, oocyte, tibia
RAB3GAP1	300	ubiquitous	marker	hair follicle, Brodmann (1909) area 23, secondary oocyte
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion
RIMS1	175	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
PROK2	159	broad	marker	blood, bone marrow, trabecular bone tissue
SOX2-OT	186	broad	marker	corpus callosum, subthalamic nucleus, inferior vagus X ganglion
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
FEZF1	52	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, hypothalamus, caudate nucleus
ADCY8	125	ubiquitous	marker	lateral nuclear group of thalamus, dorsal motor nucleus of vagus nerve, caput epididymis
TMTC1	257	ubiquitous	marker	dorsal root ganglion, lateral nuclear group of thalamus, trigeminal ganglion
DERA	288	ubiquitous	marker	secondary oocyte, jejunal mucosa, nephron tubule
OTUD4	295	ubiquitous	marker	middle frontal gyrus, Brodmann (1909) area 10, paraflocculus
VPS50	257	ubiquitous	yes	calcaneal tendon, endothelial cell, tibialis anterior
LDAH	254	ubiquitous	marker	adrenal tissue, male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans
DCC	154	broad	marker	cortical plate, right testis, left testis
PPCDC	224	ubiquitous	marker	blood, granulocyte, primordial germ cell in gonad
DMXL2	269	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell
RPS20P11
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3B	5,712
FGFR1	5,693
CHD7	4,819
AXL	4,443
PHIP	3,057
PNPLA6	2,676
ADCY8	2,527
OTUD4	2,337
SEMA3A	2,069
RAB3GAP1	2,039

Intra-cohort edges

A	B	Sources
ANOS1	CHD7	string_interaction
ANOS1	FEZF1	string_interaction
ANOS1	FGFR1	biogrid_interaction, intact, string_interaction
ANOS1	FLRT3	string_interaction
ANOS1	GNRH1	string_interaction
ANOS1	GNRHR	string_interaction
ANOS1	HESX1	string_interaction
ANOS1	PROK2	string_interaction
ANOS1	PROKR2	string_interaction
ANOS1	TACR3	string_interaction
CHD7	FEZF1	string_interaction
CHD7	GNRHR	string_interaction
CHD7	PROK2	string_interaction
CHD7	PROKR2	string_interaction
CHD7	SEMA3E	string_interaction
CHD7	TACR3	string_interaction
DMXL2	OTUD4	string_interaction
DMXL2	PNPLA6	string_interaction
DMXL2	RAB3GAP1	biogrid_interaction, string_interaction
DMXL2	RAB3GAP2	string_interaction
FEZF1	FLRT3	string_interaction
FEZF1	GNRHR	string_interaction
FEZF1	PROK2	string_interaction
FEZF1	PROKR2	string_interaction
FEZF1	TACR3	string_interaction
FGFR1	GNRHR	string_interaction
FGFR1	KL	string_interaction
FGFR1	KLB	biogrid_interaction, intact, string_interaction
FGFR1	PROK2	string_interaction
FGFR1	PROKR2	string_interaction
FGFR1	SPRY4	string_interaction
FGFR1	TACR3	string_interaction
FLRT3	PROKR2	string_interaction
FLRT3	SPRY4	string_interaction
FSHR	GNRH1	string_interaction
FSHR	GNRHR	string_interaction
GNRH1	GNRHR	string_interaction
GNRH1	PROK2	string_interaction
GNRH1	PROKR2	string_interaction
GNRH1	TACR3	string_interaction
GNRHR	PROK2	string_interaction
HESX1	PROKR2	string_interaction
PROK2	PROKR2	string_interaction
PROK2	TACR3	string_interaction
PROKR2	PROP1	string_interaction
RAB3GAP1	RAB3GAP2	biogrid_interaction, intact, string_interaction
SEMA3A	TACR3	string_interaction

Structural data

PDB: 23 · AlphaFold-only: 16 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHIP	Q8WWQ0	146
FGFR1	P11362	83
POLR3B	Q9NW08	29
DCC	P43146	9
KL	Q9UEF7	6
KLB	Q86Z14	5
FSHR	P23945	5
AXL	P30530	4
TACR3	P29371	3
CHD7	Q9P2D1	3
FLRT3	Q9NZU0	3
SRA1	Q9HD15	2
WDR11	Q9BZH6	2
GNRH1	P01148	2
PELI2	Q9HAT8	2
SPRY4	Q9C004	1
RAB3GAP1	Q15042	1
RAB3GAP2	Q9H2M9	1
RIMS1	Q86UR5	1
PPCDC	Q96CD2	1
GNRHR	P30968	1
HESX1	Q9UBX0	1
ANOS1	P23352	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DERA	Q9Y315	95.99
LDAH	Q9H6V9	90.59
TMTC1	Q8IUR5	88.13
SEMA3E	O15041	84.62
SEMA3A	Q14563	84.50
PROKR2	Q8NFJ6	78.50
ADCY8	P40145	71.82
VPS50	Q96JG6	71.19
PROP1	O75360	70.74
PNPLA6	Q8IY17	69.75
PROK2	Q9HC23	69.22
LHX3	Q9UBR4	68.68
TENT4A	Q5XG87	62.58
FEZF1	A0PJY2	56.91
OTUD4	Q01804	49.68
DMXL2	Q8TDJ6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 152. Enrichment computed across 41 evidence-associated genes (29 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 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hormone ligand-binding receptors	3	98.5×	5e-04	FSHR, GNRH1, GNRHR
Downstream signaling of activated FGFR1	3	56.3×	0.001	FGFR1, FLRT3, KL
FGFR1c and Klotho ligand binding and activation	2	196.9×	0.002	FGFR1, KL
Negative regulation of FGFR1 signaling	3	38.1×	0.002	FGFR1, ANOS1, KL
G alpha (q) signalling events	5	9.9×	0.004	TACR3, PROKR2, PROK2, GNRH1, GNRHR
PI3K Cascade	3	28.1×	0.004	KLB, FGFR1, KL
FGFR1c ligand binding and activation	2	52.5×	0.014	FGFR1, ANOS1
Phospholipase C-mediated cascade: FGFR1	2	46.3×	0.016	FGFR1, KL
PI-3K cascade:FGFR1	2	35.8×	0.021	FGFR1, KL
SHC-mediated cascade:FGFR1	2	34.2×	0.021	FGFR1, KL
Constitutive Signaling by Aberrant PI3K in Cancer	3	13.1×	0.021	KLB, FGFR1, KL
FRS-mediated FGFR1 signaling	2	31.5×	0.023	FGFR1, KL
Semaphorin interactions	2	27.2×	0.028	SEMA3A, SEMA3E
Signaling by FGFR	2	23.9×	0.033	KLB, ANOS1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	3	10.0×	0.033	KLB, FGFR1, KL
Signaling by FGFR1 amplification mutants	1	196.9×	0.045	FGFR1
FGFR1 ligand binding and activation	1	196.9×	0.045	ANOS1
betaKlotho-mediated ligand binding	1	131.3×	0.061	KLB
Downstream signaling of activated FGFR4	1	131.3×	0.061	KLB
COPI-independent Golgi-to-ER retrograde traffic	2	14.3×	0.065	RAB3GAP1, RAB3GAP2
PIP3 activates AKT signaling	3	6.9×	0.066	KLB, FGFR1, KL
Signaling by plasma membrane FGFR1 fusions	1	98.5×	0.070	FGFR1
RAF/MAP kinase cascade	3	6.3×	0.076	KLB, FGFR1, KL
DSCAM interactions	1	78.8×	0.080	DCC
Tachykinin receptors bind tachykinins	1	65.6×	0.092	TACR3
Glycerophospholipid catabolism	1	56.3×	0.102	PNPLA6
Coenzyme A biosynthesis	1	49.2×	0.102	PPCDC
IGF1R signaling cascade	1	49.2×	0.102	KLB
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	49.2×	0.102	FGFR1
FGFR1b ligand binding and activation	1	43.8×	0.102	FGFR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 39 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	3	216.1×	1e-04	KLB, FGFR1, KL
axon guidance	6	13.9×	9e-04	SEMA3A, SEMA3E, FEZF1, DCC, FLRT3, ANOS1
establishment of protein localization to endoplasmic reticulum membrane	2	288.1×	0.002	RAB3GAP1, RAB3GAP2
olfactory bulb development	3	58.9×	0.002	SEMA3A, CHD7, FEZF1
somatotropin secreting cell differentiation	2	216.1×	0.002	LHX3, PROP1
positive regulation of protein lipidation	2	216.1×	0.002	RAB3GAP1, RAB3GAP2
positive regulation of endoplasmic reticulum tubular network organization	2	216.1×	0.002	RAB3GAP1, RAB3GAP2
chordate embryonic development	2	144.0×	0.004	CHD7, FGFR1
nose development	2	123.5×	0.005	CHD7, HESX1
neuron migration	4	13.7×	0.008	SEMA3A, DCC, FGFR1, AXL
vagina development	2	78.6×	0.011	TACR3, AXL
fibroblast growth factor receptor signaling pathway	3	22.0×	0.012	FGFR1, FLRT3, KL
head development	2	61.7×	0.015	WDR11, FLRT3
gonad development	2	57.6×	0.016	FSHR, HESX1
negative regulation of apoptotic process	6	5.3×	0.023	PHIP, PROK2, GNRH1, LHX3, AXL, PROP1
positive regulation of autophagosome assembly	2	41.1×	0.028	RAB3GAP1, RAB3GAP2
motor neuron axon guidance	2	36.0×	0.035	SEMA3A, LHX3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	4	8.0×	0.035	SEMA3E, FGFR1, FSHR, AXL
negative chemotaxis	2	33.2×	0.037	SEMA3A, SEMA3E
right ventricular compact myocardium morphogenesis	1	432.1×	0.038	CHD7
proepicardium cell migration involved in pericardium morphogenesis	1	432.1×	0.038	FLRT3
negative regulation of immature T cell proliferation	1	432.1×	0.038	GNRH1
2’-deoxyribonucleoside catabolic process	1	432.1×	0.038	DERA
deoxyribose phosphate catabolic process	1	432.1×	0.038	DERA
regulation of acetylcholine metabolic process	1	432.1×	0.038	FSHR
regulation of protein K48-linked deubiquitination	1	432.1×	0.038	OTUD4
primary ovarian follicle growth	1	216.1×	0.039	FSHR
deoxyribonucleotide catabolic process	1	216.1×	0.039	DERA
regulation of platelet-derived growth factor receptor signaling pathway	1	216.1×	0.039	FSHR
medial motor column neuron differentiation	1	216.1×	0.039	LHX3

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Progesterone	Approved (phase 4)
Desogestrel	Phase 3 (in late-stage trials)
Estradiol	Phase 3 (in late-stage trials)
Ethinyl Estradiol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Metreleptin.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 36

Druggability breadth: 13 of 41 evidence-associated genes (32%) 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
TACR3	APREPITANT
FGFR1	PONATINIB
GNRHR	GONADORELIN
AXL	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
AXL	59	4
GNRHR	12	4
TACR3	9	4
ADCY8	1	2
SEMA3A	0	0
SEMA3E	0	0
SRA1	0	0
WDR11	0	0
KLB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APREPITANT	4	TACR3
FEZOLINETANT	4	TACR3
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	AXL, FGFR1
FEDRATINIB	4	AXL, FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	AXL, FGFR1
SORAFENIB	4	AXL, FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	AXL, FGFR1
CABOZANTINIB	4	AXL, FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	AXL, FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	AXL, FGFR1
DASATINIB	4	AXL, FGFR1
MIDOSTAURIN	4	AXL, FGFR1
GONADORELIN	4	GNRHR
CETRORELIX	4	GNRHR
LEUPROLIDE	4	GNRHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
AXL	701	Binding:698, Functional:3
GNRHR	302	Binding:248, Functional:54
TACR3	266	Binding:217, Functional:48, ADMET:1
FSHR	43	Functional:26, Binding:17
ADCY8	31	Binding:28, Functional:2, ADMET:1
PHIP	17	Binding:17
PROKR2	9	Functional:5, Binding:4
TENT4A	4	Binding:4
DERA	4	Binding:4
PNPLA6	1	Binding:1
KL	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TENT4A	2.7.7.19	polynucleotide adenylyltransferase
DERA	4.1.2.4	deoxyribose-phosphate aldolase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
AXL	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TACR3	266
FGFR1	1,465
GNRHR	302
AXL	701

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; 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)
APREPITANT	4	TACR3
FEZOLINETANT	4	TACR3
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	AXL, FGFR1
FEDRATINIB	4	AXL, FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	AXL, FGFR1
SORAFENIB	4	AXL, FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	AXL, FGFR1
CABOZANTINIB	4	AXL, FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	AXL, FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	AXL, FGFR1
DASATINIB	4	AXL, FGFR1
MIDOSTAURIN	4	AXL, FGFR1
GONADORELIN	4	GNRHR
CETRORELIX	4	GNRHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	TACR3, FGFR1, GNRHR, AXL
B	Phased (≥1) drug, not yet approved	1	ADCY8
C	Druggable family + PDB, no drug	4	DCC, FLRT3, FSHR, ANOS1
D	Druggable family + AlphaFold only, no drug	6	SEMA3A, SEMA3E, PROKR2, TENT4A, DERA, OTUD4
E	Difficult family or no structure, no drug	26	SRA1, WDR11, KLB, SPRY4, PHIP, PNPLA6, RAB3GAP1, RAB3GAP2, RIMS1, PROK2 (+16 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KLB	0	FGFR1
GNRH1	0	GNRHR
ANOS1	0	FGFR1
KL	1	FGFR1
SEMA3A	0	—
SEMA3E	0	—
SRA1	0	—
WDR11	0	—
SPRY4	0	—
PHIP	17	—
PROKR2	9	—
PNPLA6	1	—
TENT4A	4	—
RAB3GAP1	0	—
RAB3GAP2	0	—
RIMS1	0	—
PROK2	0	—
SOX2-OT	0	—
CHD7	0	—
FEZF1	0	—
TMTC1	0	—
DERA	4	—
OTUD4	0	—
VPS50	0	—
LDAH	0	—
DCC	0	—
PPCDC	0	—
DMXL2	0	—
POLR3B	0	—
RPS20P11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 34.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE2	5
PHASE4	3
PHASE1/PHASE2	2
PHASE1	2
PHASE3	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT00589654	Not specified	ACTIVE_NOT_RECRUITING	Menstrual Cycle Maintenance and Quality of Life: A Prospective Study
NCT01500447	Not specified	RECRUITING	Inherited Reproductive Disorders
NCT04424576	Not specified	RECRUITING	Ovarian Morphology in Girls
NCT06280807	Not specified	RECRUITING	Observation of Environment and Reproductive-Endocrine Effects
NCT06800170	Not specified	RECRUITING	Treatment of Menstrual Cycle Alterations in Adolescents
NCT07015476	Not specified	RECRUITING	Retrospective Observational Evaluation of the Bone Mineral Density Outcome in Young Women With Amenorrhea
NCT07612735	Not specified	NOT_YET_RECRUITING	Effects of Resistance Training on Women With Functional Hypothalamic Amenorrhea
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants
NCT00243607	Not specified	COMPLETED	Hydrotherapy Against Menopausal Symptoms in Breast Cancer Survivors
NCT00260286	Not specified	COMPLETED	Effects of Gynecological Age on LH Sensitivity to Energy Availability
NCT00456274	Not specified	UNKNOWN	Baselines in Reproductive Disorders
NCT01423487	Not specified	WITHDRAWN	Efficacy and Safety of Metformin in Preventing Patients With Risperidone From Weight Gain and Amenorrhea
NCT01511588	Not specified	COMPLETED	Hormonal Regulation of Puberty and Fertility
NCT01785719	Not specified	COMPLETED	Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss
NCT01927432	Not specified	COMPLETED	Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
NCT02224976	Not specified	COMPLETED	Effect of Intense Training on Ovarian Function and Bone Turnover
NCT04135729	Not specified	COMPLETED	Mental Health in Fitness Instructors
NCT04938622	Not specified	COMPLETED	Bioenergetics of Exercise-Induced Menstrual Disturbances
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ESTRADIOL	4	1
ESTROGENS, CONJUGATED	4	1
ETHINYL ESTRADIOL	4	1
GONADORELIN ACETATE	4	1
LEUPROLIDE	4	1
METFORMIN	4	1
METRELEPTIN	4	1
TELAPRISTONE ACETATE	3	2
ASOPRISNIL	3	1
CYPROTERONE ACETATE	3	1
ESTROGEN	3	1
STARCH	3	1
CHEMBL4303251	0	1
CHEMBL4558169	0	1
CHEMBL2370644	0	1