Infertility disorder

disease

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Also known as fertility disordersinfertileSterilesterility

Summary

Infertility disorder (MONDO:0005047) is a disease (an umbrella term covering 5 Mondo subtypes) caused by MEI4 (GenCC Strong), with 22 cohort genes and 103 clinical trials. Top therapeutic interventions include follitropin, follitropin delta, and triptorelin.

At a glance

Causal gene: MEI4 (GenCC Strong)
Umbrella term: 5 Mondo subtypes
Cohort genes: 22
ClinVar variants: 23
Clinical trials: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	infertility disorder
Mondo ID	MONDO:0005047
EFO	EFO:0000545
MeSH	D007246
DOID	DOID:5223
NCIT	C3836
UMLS	C0021359
MedGen	43876
Is cancer (heuristic)	no

Also known as: fertility disorders · infertile · Sterile · sterile · sterility

Data availability: 23 ClinVar variants · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › infertility disorder

Subtypes (5): male infertility, inherited oocyte maturation defect, female infertility, pregnancy loss, recurrent, 4, SYCE1-related gametogenic 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

23 retrieved; paginated sample, class counts are floors:

13 conflicting classifications of pathogenicity, 4 uncertain significance, 3 pathogenic/likely pathogenic, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31067	NM_181426.2(CCDC39):c.357+1G>C	CCDC39	Pathogenic	criteria provided, multiple submitters, no conflicts
31698	NM_213607.3(DNAAF19):c.461A>C (p.His154Pro)	DNAAF19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
454795	NM_001369.3(DNAH5):c.6763C>T (p.Arg2255Ter)	DNAH5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16023	NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)	GNRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3401	NM_015102.5(NPHP4):c.2044C>T (p.Arg682Ter)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1699948	NM_001042697.2(ZSWIM7):c.176C>T (p.Ser59Leu)	ZSWIM7	Likely pathogenic	no assertion criteria provided
422609	NM_172095.4(CATSPER2):c.920G>C (p.Trp307Ser)	CATSPER2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219537	NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
53733	NM_000492.4(CFTR):c.3409A>G (p.Met1137Val)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
53774	NM_000492.4(CFTR):c.358G>A (p.Ala120Thr)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7126	NM_000492.4(CFTR):c.1523T>G (p.Phe508Cys)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7229	NM_000492.4(CFTR):c.2991G>C (p.Leu997Phe)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
454639	NM_001277115.2(DNAH11):c.1108C>A (p.Leu370Met)	DNAH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220051	NM_001369.3(DNAH5):c.12251G>A (p.Arg4084Gln)	DNAH5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238981	NM_001369.3(DNAH5):c.5413C>T (p.Arg1805Cys)	DNAH5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362891	NM_023110.3(FGFR1):c.2465G>A (p.Arg822His)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45153	NM_004999.4(MYO6):c.3176G>C (p.Arg1059Thr)	MYO6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3449	NM_144773.4(PROKR2):c.518T>G (p.Leu173Arg)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180150	NM_013251.4(TAC3):c.248A>G (p.His83Arg)	TAC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473106	NM_012472.6(DNAAF11):c.27T>G (p.Ile9Met)	DNAAF11	Uncertain significance	criteria provided, multiple submitters, no conflicts
216677	NM_012144.4(DNAI1):c.1948C>T (p.Arg650Cys)	DNAI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
872981	NM_032940.3(POLR2C):c.545T>C (p.Val182Ala)	POLR2C	Uncertain significance	no assertion criteria provided
161609	NM_003243.5(TGFBR3):c.2519C>T (p.Thr840Met)	TGFBR3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 45 · 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
MEI4	Strong	Semidominant	infertility disorder
RNF212B	Moderate	Autosomal recessive	infertility disorder
SPATA22	Moderate	Autosomal recessive	infertility disorder	2
SYCP3	Moderate	Autosomal dominant	infertility disorder	2
RABL2A	Limited	Autosomal dominant	infertility disorder

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYCP3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
TAC3	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
TGFBR3	Orphanet:231160	Familial cerebral saccular aneurysm
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
DNAAF11	Orphanet:244	Primary ciliary dyskinesia
CATSPER2	Orphanet:94064	Deafness-infertility syndrome
CFTR	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CFTR	Orphanet:48	Congenital bilateral absence of vas deferens
CFTR	Orphanet:498359	Aquagenic palmoplantar keratoderma
CFTR	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:60033	Idiopathic bronchiectasis
CFTR	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis
NPHP4	Orphanet:3156	Senior-Loken syndrome
NPHP4	Orphanet:93592	Juvenile nephronophthisis
CCDC39	Orphanet:244	Primary ciliary dyskinesia
ZSWIM7	Orphanet:243	46,XX gonadal dysgenesis
ZSWIM7	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
DNAH11	Orphanet:244	Primary ciliary dyskinesia
DNAH5	Orphanet:244	Primary ciliary dyskinesia
DNAI1	Orphanet:244	Primary ciliary dyskinesia
DNAAF19	Orphanet:244	Primary ciliary dyskinesia
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
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly
FGFR1	Orphanet:99798	Oligodontia
GNRHR	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
MYO6	Orphanet:228012	Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
MYO6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

22 cohort genes, 22 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	22

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYCP3	HGNC:18130	ENSG00000139351	Q8IZU3	Synaptonemal complex protein 3	gencc
RNF212B	HGNC:20438	ENSG00000215277	A8MTL3	E3 ubiquitin-protein ligase RNF212B	gencc
SPATA22	HGNC:30705	ENSG00000141255	Q8NHS9	Spermatogenesis-associated protein 22	gencc
MEI4	HGNC:43638	ENSG00000269964	A8MW99	Meiosis-specific protein MEI4	gencc
RABL2A	HGNC:9799	ENSG00000144134	Q9UBK7	Rab-like protein 2A	gencc
TAC3	HGNC:11521	ENSG00000166863	Q9UHF0	Tachykinin-3	clinvar
TGFBR3	HGNC:11774	ENSG00000069702	Q03167	Transforming growth factor beta receptor type 3	clinvar
PROKR2	HGNC:15836	ENSG00000101292	Q8NFJ6	Prokineticin receptor 2	clinvar
DNAAF11	HGNC:16725	ENSG00000129295	Q86X45	Dynein axonemal assembly factor 11	clinvar
CATSPER2	HGNC:18810	ENSG00000166762	Q96P56	Cation channel sperm-associated protein 2	clinvar
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	clinvar
NPHP4	HGNC:19104	ENSG00000131697	O75161	Nephrocystin-4	clinvar
CCDC39	HGNC:25244	ENSG00000284862	Q9UFE4	Coiled-coil domain-containing protein 39	clinvar
ZSWIM7	HGNC:26993	ENSG00000214941	Q19AV6	Zinc finger SWIM domain-containing protein 7	clinvar
DNAH11	HGNC:2942	ENSG00000105877	Q96DT5	Dynein axonemal heavy chain 11	clinvar
DNAH5	HGNC:2950	ENSG00000039139	Q8TE73	Dynein axonemal heavy chain 5	clinvar
DNAI1	HGNC:2954	ENSG00000122735	Q9UI46	Dynein axonemal intermediate chain 1	clinvar
DNAAF19	HGNC:32700	ENSG00000167131	Q8IW40	Dynein axonemal assembly factor 19	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
GNRHR	HGNC:4421	ENSG00000109163	P30968	Gonadotropin-releasing hormone receptor	clinvar
MYO6	HGNC:7605	ENSG00000196586	Q9UM54	Unconventional myosin-VI	clinvar
POLR2C	HGNC:9189	ENSG00000102978	P19387	DNA-directed RNA polymerase II subunit RPB3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYCP3	Synaptonemal complex protein 3	Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase.
RNF212B	E3 ubiquitin-protein ligase RNF212B	Ubiquitin E3 ligase that acts as a crucial factor for crossing-over (CO) formation during meiosis.
SPATA22	Spermatogenesis-associated protein 22	Meiosis-specific protein required for homologous recombination in meiosis I.
MEI4	Meiosis-specific protein MEI4	Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination.
RABL2A	Rab-like protein 2A	Small GTPase that plays an essential role in male fertility, sperm intra-flagellar transport, and tail assembly.
TAC3	Tachykinin-3	Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.
TGFBR3	Transforming growth factor beta receptor type 3	Cell surface receptor that regulates diverse cellular processes including cell proliferation, differentiation, migration, and apoptosis.
PROKR2	Prokineticin receptor 2	Receptor for prokineticin 2.
DNAAF11	Dynein axonemal assembly factor 11	Involved in dynein arm assembly, is important for expression and transporting outer dynein arm (ODA) proteins from the cytoplasm to the cilia.
CATSPER2	Cation channel sperm-associated protein 2	Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel, that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acro…
CFTR	Cystic fibrosis transmembrane conductance regulator	Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.
NPHP4	Nephrocystin-4	Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.
CCDC39	Coiled-coil domain-containing protein 39	Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella.
ZSWIM7	Zinc finger SWIM domain-containing protein 7	Involved in early stages of the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.
DNAH11	Dynein axonemal heavy chain 11	Force generating protein required for cilia beating in respiratory epithelia.
DNAH5	Dynein axonemal heavy chain 5	Force generating protein of respiratory cilia.
DNAI1	Dynein axonemal intermediate chain 1	Component of dynein, a family of motor proteins essential for movement along microtubules.
DNAAF19	Dynein axonemal assembly factor 19	Dynein-attachment factor required for cilia motility.
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.
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).
MYO6	Unconventional myosin-VI	Myosins are actin-based motor molecules with ATPase activity.
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.

Protein-family classification

Druggable: 5 · Difficult: 4 · Unknown: 13 · Druggable fraction: 0.23

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
Ion channel	1	5.1×	0.578
Transporter	1	3.5×	0.578
GPCR	2	2.2×	0.578
Scaffold/PPI	2	1.6×	0.641
Kinase	1	1.3×	0.647
Other/Unknown	13	1.1×	0.647
Transcription factor	2	0.8×	0.765

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYCP3	Other/Unknown	no		XLR/SYCP3/FAM9_dom, XLR/SYCP3
RNF212B	Transcription factor	no		Znf_RING_CS, Zip3/RNF212-like
SPATA22	Other/Unknown	no		Spata22
MEI4	Other/Unknown	no		MEI4
RABL2A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
TAC3	Other/Unknown	no		Neurokinin-B/TAC3, Tachy_Neuro_lke_CS
TGFBR3	Other/Unknown	no		ZP_dom, ZP_dom_CS, ZP-C_dom
PROKR2	GPCR	yes		GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM
DNAAF11	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, CS_dom
CATSPER2	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, CatSper2
CFTR	Transporter	yes	2.7.4.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, CFTR/ABCC7
NPHP4	Other/Unknown	no		NPHP4, Ig_NPHP4_4th, Ig_NPHP4_3rd
CCDC39	Other/Unknown	no		CCDC39
ZSWIM7	Transcription factor	no		Znf_SWIM
DNAH11	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DNAH5	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DNAI1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
DNAAF19	Other/Unknown	no		RPAP3-like_C, Dynein_attach_N, CC103
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
GNRHR	GPCR	yes		GPCR_Rhodpsn, GphnRH_fam_rcpt, GPCR_Rhodpsn_7TM
MYO6	Scaffold/PPI	no		Myosin_head_motor_dom-like, SH3_Myosin, Myosin_S1_N
POLR2C	Other/Unknown	no		DNA-dir_RNA_pol_30-40kDasu_CS, DNA-dir_RNA_pol_insert, DNA-dir_RNA_pol_RpoA/D/Rpb3

Expression context

Cohort genes with no expression data: 0.

18 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)	22
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	6
bronchial epithelial cell	4
left testis	3
primordial germ cell in gonad	3
male germ line stem cell (sensu Vertebrata) in testis	3
adenohypophysis	3
right testis	2
secondary oocyte	2
sperm	2
islet of Langerhans	2
right lobe of thyroid gland	2
epithelium of bronchus	2
bronchus	2
kidney epithelium	1
fallopian tube	1
decidua	1
placenta	1
metanephric glomerulus	1
renal glomerulus	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYCP3	170	tissue_specific	marker	right testis, left testis, secondary oocyte
RNF212B	157	tissue_specific	marker	kidney epithelium, sperm, primordial germ cell in gonad
SPATA22	161	tissue_specific	marker	sperm, right testis, left testis
MEI4	52	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, islet of Langerhans
RABL2A	134	broad	marker	right uterine tube, fallopian tube, right lobe of thyroid gland
TAC3	162	broad	marker	decidua, primordial germ cell in gonad, placenta
TGFBR3	288	ubiquitous	marker	renal glomerulus, metanephric glomerulus, synovial joint
PROKR2	32	tissue_specific	yes	cortical plate, ganglionic eminence, ventricular zone
DNAAF11	219	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
CATSPER2	220	tissue_specific	yes	cerebellar vermis, right hemisphere of cerebellum, cerebellar cortex
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas
NPHP4	165	ubiquitous	marker	right uterine tube, adenohypophysis, right lobe of thyroid gland
CCDC39	132	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, endometrium
ZSWIM7	250	ubiquitous	marker	tendon of biceps brachii, right adrenal gland cortex, left adrenal gland
DNAH11	163	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
DNAH5	184	broad	marker	bronchial epithelial cell, bronchus, oviduct epithelium
DNAI1	170	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
DNAAF19	130	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, testis
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
GNRHR	121	tissue_specific	yes	adrenal tissue, adenohypophysis, male germ line stem cell (sensu Vertebrata) in testis
MYO6	278	ubiquitous	marker	amniotic fluid, medial globus pallidus, corpus callosum
POLR2C	298	ubiquitous	marker	islet of Langerhans, secondary oocyte, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
POLR2C	6,325
FGFR1	5,693
MYO6	2,972
TGFBR3	2,412
RABL2A	2,245
DNAH5	1,834
DNAH11	1,666
SYCP3	1,619
NPHP4	1,579

Intra-cohort edges

A	B	Sources
CCDC39	DNAAF11	string_interaction
CCDC39	DNAAF19	string_interaction
CCDC39	DNAH11	string_interaction
CCDC39	DNAH5	string_interaction
CCDC39	DNAI1	string_interaction
CFTR	MYO6	biogrid_interaction, intact
DNAAF11	DNAAF19	string_interaction
DNAAF11	DNAH11	string_interaction
DNAAF11	DNAI1	string_interaction
DNAAF19	DNAH11	string_interaction
DNAAF19	DNAI1	string_interaction
DNAH11	DNAI1	string_interaction
DNAH5	DNAI1	string_interaction
FGFR1	GNRHR	string_interaction
FGFR1	PROKR2	string_interaction
FGFR1	TGFBR3	biogrid_interaction
GNRHR	TAC3	string_interaction
PROKR2	TAC3	string_interaction
SPATA22	SYCP3	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 11 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83
CFTR	P13569	58
POLR2C	P19387	21
MYO6	Q9UM54	8
TAC3	Q9UHF0	2
SYCP3	Q8IZU3	1
TGFBR3	Q03167	1
CCDC39	Q9UFE4	1
DNAH5	Q8TE73	1
DNAI1	Q9UI46	1
GNRHR	P30968	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZSWIM7	Q19AV6	92.13
DNAAF19	Q8IW40	80.42
RABL2A	Q9UBK7	79.80
PROKR2	Q8NFJ6	78.50
DNAAF11	Q86X45	74.44
NPHP4	O75161	72.44
MEI4	A8MW99	70.83
CATSPER2	Q96P56	69.83
RNF212B	A8MTL3	67.10
SPATA22	Q8NHS9	61.02
DNAH11	Q96DT5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 149. Enrichment computed across 22 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR1b ligand binding and activation	2	230.7×	0.005	TGFBR3, FGFR1
FGFR1c ligand binding and activation	2	138.4×	0.007	TGFBR3, FGFR1
Signaling by FGFR	2	62.9×	0.022	TGFBR3, POLR2C
G alpha (q) signalling events	3	15.7×	0.029	TAC3, PROKR2, GNRHR
Signaling by FGFR1 amplification mutants	1	519.1×	0.048	FGFR1
FGFR1 ligand binding and activation	1	519.1×	0.048	TGFBR3
RHO GTPases regulate CFTR trafficking	1	346.1×	0.052	CFTR
TGFBR3 regulates FGF2 signaling	1	346.1×	0.052	TGFBR3
FGFR1c and Klotho ligand binding and activation	1	259.6×	0.052	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	259.6×	0.052	FGFR1
TGFBR3 regulates activin signaling	1	259.6×	0.052	TGFBR3
Tachykinin receptors bind tachykinins	1	173.0×	0.072	TAC3
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	129.8×	0.076	FGFR1
TGFBR3 regulates TGF-beta signaling	1	129.8×	0.076	TGFBR3
Sperm Motility And Taxes	1	115.3×	0.076	CATSPER2
Signaling by activated point mutants of FGFR1	1	86.5×	0.076	FGFR1
Gap junction degradation	1	86.5×	0.076	MYO6
Hormone ligand-binding receptors	1	86.5×	0.076	GNRHR
TGFBR3 PTM regulation	1	86.5×	0.076	TGFBR3
Signaling by FGFR1	1	74.2×	0.076	TGFBR3
RHOBTB GTPase Cycle	1	74.2×	0.076	MYO6
Signaling by Activin	1	69.2×	0.076	TGFBR3
FGFR2 mutant receptor activation	1	69.2×	0.076	POLR2C
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	69.2×	0.076	MYO6
Phospholipase C-mediated cascade: FGFR1	1	61.1×	0.076	FGFR1
Signaling by FGFR2 IIIa TM	1	54.6×	0.076	POLR2C
Signaling by Hippo	1	49.4×	0.076	NPHP4
Trafficking of AMPA receptors	1	49.4×	0.076	MYO6
Downstream signaling of activated FGFR1	1	49.4×	0.076	FGFR1
Signal transduction by L1	1	47.2×	0.076	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 22 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
flagellated sperm motility	7	37.2×	9e-08	DNAAF11, CATSPER2, NPHP4, CCDC39, DNAH11, DNAH5, DNAI1
epithelial cilium movement involved in determination of left/right asymmetry	4	235.7×	2e-07	DNAAF11, CCDC39, DNAH11, DNAAF19
cilium movement	5	89.1×	2e-07	DNAAF11, CCDC39, DNAH5, DNAI1, DNAAF19
epithelial cilium movement involved in extracellular fluid movement	4	139.3×	8e-07	DNAAF11, DNAH5, DNAI1, DNAAF19
outer dynein arm assembly	4	133.2×	8e-07	DNAAF11, DNAH5, DNAI1, DNAAF19
axonemal dynein complex assembly	3	143.6×	4e-05	DNAAF11, CCDC39, DNAAF19
determination of left/right symmetry	4	46.4×	4e-05	DNAH11, DNAH5, DNAI1, DNAAF19
inner dynein arm assembly	3	121.0×	5e-05	DNAAF11, CCDC39, DNAAF19
homologous chromosome pairing at meiosis	3	82.1×	1e-04	RNF212B, SPATA22, MEI4
establishment of localization in cell	4	29.2×	2e-04	DNAAF11, CFTR, CCDC39, DNAH5
protein localization to motile cilium	2	306.4×	3e-04	DNAAF11, DNAH11
determination of digestive tract left/right asymmetry	2	255.3×	4e-04	CCDC39, DNAAF19
reproductive system development	2	218.9×	5e-04	DNAAF11, SPATA22
regulation of cilium beat frequency	2	191.5×	7e-04	CCDC39, DNAH11
cerebrospinal fluid circulation	2	80.6×	0.004	DNAAF11, CCDC39
sperm capacitation	2	61.3×	0.006	CATSPER2, CFTR
cilium movement involved in cell motility	2	61.3×	0.006	DNAH11, DNAH5
positive regulation of cardiac muscle cell proliferation	2	56.7×	0.006	TGFBR3, FGFR1
motile cilium assembly	2	52.8×	0.007	DNAAF11, CCDC39
cardiac muscle cell proliferation	2	52.8×	0.007	TGFBR3, FGFR1
epicardium-derived cardiac fibroblast cell development	1	766.0×	0.013	TGFBR3
protein localization to cilium	2	36.5×	0.013	DNAAF11, CCDC39
cellular response to hormone stimulus	2	34.8×	0.013	PROKR2, GNRHR
gonadotropin secretion	1	383.0×	0.016	GNRHR
response to luteinizing hormone	1	383.0×	0.016	TGFBR3
determination of left/right asymmetry in nervous system	1	383.0×	0.016	DNAH11
spermatocyte division	1	383.0×	0.016	SPATA22
vitamin D3 metabolic process	1	383.0×	0.016	FGFR1
positive regulation of mitotic cell cycle DNA replication	1	383.0×	0.016	FGFR1
positive regulation of parathyroid hormone secretion	1	383.0×	0.016	FGFR1

Therapeutics

Drugs indicated for this disease

2 approved, 40 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)
Follitropin Beta	Approved (phase 4)
Acetylcysteine	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Cetrorelix	Phase 3 (in late-stage trials)
Corifollitropin Alfa	Phase 3 (in late-stage trials)
Danazol	Phase 3 (in late-stage trials)
Desogestrel	Phase 3 (in late-stage trials)
Diclofenac	Phase 3 (in late-stage trials)
Dydrogesterone	Phase 3 (in late-stage trials)
Estradiol	Phase 3 (in late-stage trials)
Estradiol Valerate	Phase 3 (in late-stage trials)
Follitropin	Phase 3 (in late-stage trials)
Follitropin Alfa	Phase 3 (in late-stage trials)
Follitropin Delta	Phase 3 (in late-stage trials)
Ganirelix	Phase 3 (in late-stage trials)
Gonadotropin, Chorionic	Phase 3 (in late-stage trials)
Goserelin	Phase 3 (in late-stage trials)
KISSPEPTIN-10	Phase 3 (in late-stage trials)
Letrozole	Phase 3 (in late-stage trials)
Leuprolide	Phase 3 (in late-stage trials)
Lh (Menotropins)	Phase 3 (in late-stage trials)
Lutropin Alfa	Phase 3 (in late-stage trials)
Medroxyprogesterone Acetate	Phase 3 (in late-stage trials)
Menotropins	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Midazolam	Phase 3 (in late-stage trials)
Nolasiban	Phase 3 (in late-stage trials)
Orlistat	Phase 3 (in late-stage trials)
Parnaparin Sodium	Phase 3 (in late-stage trials)
Prasterone	Phase 3 (in late-stage trials)
Progesterone	Phase 3 (in late-stage trials)
Resveratrol	Phase 3 (in late-stage trials)
Simethicone	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Soybean Oil	Phase 3 (in late-stage trials)
Tacrolimus Anhydrous	Phase 3 (in late-stage trials)
Tamoxifen	Phase 3 (in late-stage trials)
Testosterone	Phase 3 (in late-stage trials)
Triptorelin	Phase 3 (in late-stage trials)
Triptorelin Acetate	Phase 3 (in late-stage trials)
Urofollitropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcarnitine, Azathioprine, Cabergoline, Degarelix, Diosmin, Filgrastim, Folic Acid, Ginger, Heparin, Lidocaine, Nafarelin, Nimodipine, Prednisolone, Salicylic Acid, Sildenafil, Somatropin.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 19

Druggability breadth: 5 of 22 evidence-associated genes (23%) 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
CFTR	IVACAFTOR
FGFR1	PONATINIB
GNRHR	GONADORELIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
CFTR	14	4
GNRHR	12	4
SYCP3	0	0
RNF212B	0	0
SPATA22	0	0
MEI4	0	0
RABL2A	0	0
TAC3	0	0
TGFBR3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1
GNRHR	302	Binding:248, Functional:54
PROKR2	9	Functional:5, Binding:4
TAC3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase
FGFR1	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
CFTR	520
FGFR1	1,465
GNRHR	302

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CFTR	1

Chemical tractability of cohort targets

30 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)
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CFTR, FGFR1, GNRHR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	PROKR2, CATSPER2
E	Difficult family or no structure, no drug	17	SYCP3, RNF212B, SPATA22, MEI4, RABL2A, TAC3, TGFBR3, DNAAF11, NPHP4, CCDC39 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYCP3	0	—
RNF212B	0	—
SPATA22	0	—
MEI4	0	—
RABL2A	0	—
TAC3	1	—
TGFBR3	0	—
PROKR2	9	—
DNAAF11	0	—
CATSPER2	0	—
NPHP4	0	—
CCDC39	0	—
ZSWIM7	0	—
DNAH11	0	—
DNAH5	0	—
DNAI1	0	—
DNAAF19	0	—
MYO6	0	—
POLR2C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 103.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	86
PHASE4	11
PHASE3	3
PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
NCT04701034	PHASE2	COMPLETED	Intravenous Immunoglobulin and Prednisolone for RPL After ART.
NCT04850261	PHASE2	WITHDRAWN	Injection Free IVF
NCT02081924	Not specified	RECRUITING	Reproductive Hormones During Sustained Administration of Kisspeptin
NCT03085212	Not specified	ACTIVE_NOT_RECRUITING	Strategies for Pregnancy Achievement
NCT03180827	Not specified	ACTIVE_NOT_RECRUITING	Female Fertility Preservation Using Ovarian Tissue Cryopreservation Before Highly Gonadotoxic Cancer Treatment
NCT03180918	Not specified	RECRUITING	Male Fertility Preservation Using Cryopreservation of Testicular Tissue Before Highly Gonadotoxic Cancer Treatment
NCT04619524	Not specified	RECRUITING	Biomarkers of Endometrial Receptivity
NCT05173597	Not specified	RECRUITING	Real-world Evidence on Follitropin Delta Individual Dosing
NCT05740579	Not specified	RECRUITING	The Danish TURNER Cryopreservation Study
NCT05807256	Not specified	RECRUITING	Medically Assisted Fertilization Techniques in Systemic Immunoreumatologic Diseases
NCT06063551	Not specified	RECRUITING	Cryopreservation of Prepubertal Testicular Tissue for Preservation of Fertility in Young Boys With Cancer
NCT06122207	Not specified	RECRUITING	Effect of a Probiotic on the Female Genital Tract Microbiota of Participants With Fertility Disorders.
NCT06144268	Not specified	RECRUITING	Live Birth Rate After Sperm Selection Using ZyMōt Multi (850µL) Device for Intra Uterine Insemination
NCT06304220	Not specified	NOT_YET_RECRUITING	Comparison of Two PPOS Models for Pituitary Suppression
NCT06584994	Not specified	ENROLLING_BY_INVITATION	Investigating the Role of Genetics in Disease Predisposition
NCT06799507	Not specified	RECRUITING	The Effect of Mindfulness-Based Lifestyle Support Program on Infertile Women
NCT06928337	Not specified	RECRUITING	Data Collection Protocol for the Development of CHLOE-OQ, an AI Model for Assessing Oocytes Quality.
NCT07017972	Not specified	RECRUITING	Data Collection and Professional Simulated Use Study to Develop an Embryo Quality Artificial Intelligence (AI) Model
NCT01330771	Not specified	COMPLETED	Assessment of the Therapeutic Utility of r-FSH in Association With hMG-HP
NCT01330784	Not specified	COMPLETED	Assessment of the Therapeutic Utility of hMG-HP
NCT01331720	Not specified	COMPLETED	Assessment of the Effectiveness and Tolerability of Ovarian Hyperstimulation
NCT01331733	Not specified	COMPLETED	Comparative Assessment of the Clinical Utility of Ovarian Stimulation With Menotropin Versus Menotropin Plus GnRH Antagonist
NCT01406964	Not specified	COMPLETED	Chlamidia Antibodies Test for Tubal Factor Screening
NCT01533350	Not specified	COMPLETED	Receptivity Assessment of Homogeneous Endometrium in Late Follicle Phase
NCT01955356	Not specified	COMPLETED	Embryo Implantation After Induced Endometrial Injury

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FOLLITROPIN	4	2
FOLLITROPIN DELTA	4	2
TRIPTORELIN	4	2
CETRORELIX ACETATE	4	1
CORIFOLLITROPIN ALFA	4	1
DYDROGESTERONE	4	1
FOLLITROPIN ALFA	4	1
GANIRELIX ACETATE	4	1
NAFARELIN	4	1
PROGESTERONE	4	1
TESTOSTERONE	4	1
INOSITOL	3	2
BEMIPARIN SODIUM	3	1
ESTROGEN	3	1
KISSPEPTIN	2	1
CHEMBL1950780	0	2
CHEMBL4746472	0	1

Cohort genes: SYCP3, RNF212B, SPATA22, MEI4, RABL2A, TAC3, TGFBR3, PROKR2, DNAAF11, CATSPER2, CFTR, NPHP4, CCDC39, ZSWIM7, DNAH11, DNAH5, DNAI1, DNAAF19, FGFR1, GNRHR, MYO6, POLR2C
Drugs: Follitropin, Follitropin Delta, Triptorelin, Cetrorelix Acetate, Corifollitropin Alfa, Dydrogesterone, Follitropin Alfa, Ganirelix Acetate, Nafarelin, Progesterone, Testosterone, Inositol, Bemiparin, Estrogen