Male infertility

Summary

Male infertility (MONDO:0005372) is a disease (an umbrella term covering 8 Mondo subtypes) caused by SEPTIN4 (GenCC Strong), with 75 cohort genes (20 GWAS associations across 18 studies) and 125 clinical trials. The dominant Reactome pathway is PIWI-interacting RNA (piRNA) biogenesis (11 cohort genes). Top therapeutic interventions include clomiphene, alitretinoin, and artenimol.

At a glance

• Causal gene: SEPTIN4 (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 20
• ClinVar variants: 182
• Clinical trials: 125

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	male infertility
Mondo ID	MONDO:0005372
EFO	EFO:0004248
MeSH	D007248
DOID	DOID:12336
ICD-10-CM	N46
ICD-11	753457327
SNOMED CT	2904007
UMLS	C0021364
MedGen	5796
Anatomy (UBERON)	UBERON:0000079
Is cancer (heuristic)	no

Also known as: infertility disorder of male reproductive system · male reproductive system infertility · male reproductive system infertility disorder

Data availability: 182 ClinVar variants · 20 GWAS associations (18 studies) · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Related subtypes (25): benign male reproductive system neoplasm, hematocele of tunica vaginalis testis, male genital organ stricture, male genital organ vascular disease, penile disorder, testicular disorder, prostate disorder, epididymitis, hydrocele, male genital tuberculosis, spermatocele, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, cryptorchidism, diphallia, postorgasmic illness syndrome, penoscrotal transposition, congenital bilateral absence of vas deferens, posterior hypospadias, isolated micropenis, male reproductive system neoplasm, fournier gangrene, congenital agenesis of the scrotum, scrotal disorder, congenital megaprepuce, epididymis disease

Subtypes (8): infertility due to extratesticular cause, oligospermia, spermatogenic failure, partial chromosome Y deletion, male infertility with teratozoospermia due to single gene mutation, male infertility due to acephalic spermatozoa, azoospermia, oligoasthenoteratozoospermia

Genetics & variants

GWAS landscape

20 GWAS associations across 18 studies. Top hits map to 13 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs149265363	2e-16	PLCL1	G	2.99
rs184686846	3e-16	DNAJC3-DT	T	2.79
rs1043848039	6e-12	PPIAP74 - ZBBX	A	3.01
rs190342480	1e-11	RPL13AP25 - LINC02335	G	2.77
rs185620637	1e-11	ZNF490	T	2.91
rs142560854	1e-11	RPL23AP54 - RN7SKP159	?
rs188613851	2e-11	RNU1-150P - TTC33	A	2.34
rs531148189	3e-11	ROCR	A	1.93
rs558556903	4e-11	WDR95P	G	2.53
rs1228269928	3e-08	NCKAP5-AS1, NCKAP5	T	10
rs139862664	3e-08	ENO4	G	2.58
rs75957543	3e-08	UMODL1	G	1.67
rs7873478	3e-07	DMRT1	C	1.24
rs6068020	5e-07	RNU7-6P - ZFP64	?
rs10841496	5e-07	PDE3A-AS1, PDE3A	?
rs9814870	7e-07	MTHFD2P1 - HNRNPKP4	?
rs1399645	9e-07	AHCYP4 - SNORA72	?
rs186420734	1e-06	MIR548BAHG - RPL7P13	A	6.29
rs10848911	4e-06	CRACR2A	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90483468	Venkatesh SS	2025	7,479	432,508	Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum.
GCST90727109	Kim HI	2026	1,818	42,208	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90239716	Cervan-Martin M	2022	1,274	1,951	Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.
GCST90478650	Verma A	2024	827	415,693	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480420	Verma A	2024	340	104,329	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482244	Verma A	2024	340	104,329	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482243	Verma A	2024	339	53,175	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90239722	Cervan-Martin M	2022	258	1,951	Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.
GCST90436462	Zhou W	2018	236	389,094	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90727137	Kim HI	2026	173	43,853	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	18

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	2
rare (<0.01)	10
unknown	1

Functional consequences

Consequence	Count
intron_variant	11
intergenic_variant	7
5_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs149265363	2	198457702	G>C	0.001	intergenic_variant	PLCL1	2e-16	Tier 4: intronic/intergenic
rs184686846	13	95654613	T>C	0.001	intron_variant	DNAJC3-DT	3e-16	Tier 4: intronic/intergenic
rs1043848039	3	167114361	A>C,T	0	intergenic_variant	PPIAP74 - ZBBX	6e-12	Tier 4: intronic/intergenic
rs190342480	13	55016657	G>C	0.001	intergenic_variant	RPL13AP25 - LINC02335	1e-11	Tier 4: intronic/intergenic
rs185620637	19	12592728	T>C	0.001	intron_variant	ZNF490	1e-11	Tier 4: intronic/intergenic
rs142560854	8	5726005	G>A,T	0.05	intergenic_variant	RPL23AP54 - RN7SKP159	1e-11	Tier 4: intronic/intergenic
rs188613851	5	40361194	A>C,G	0.001	intergenic_variant	RNU1-150P - TTC33	2e-11	Tier 4: intronic/intergenic
rs531148189	17	72013411	A>G	0.003	intron_variant	ROCR	3e-11	Tier 4: intronic/intergenic
rs558556903	13	31082691	G>T	0.001	intron_variant	WDR95P	4e-11	Tier 4: intronic/intergenic
rs1228269928	2	132923776	A>G,T		intron_variant	NCKAP5-AS1, NCKAP5	3e-08	Tier 4: intronic/intergenic
rs139862664	10	116879589	C>G	0.007	intron_variant	ENO4	3e-08	Tier 4: intronic/intergenic
rs75957543	21	42081234	G>A,C,T	0.013	intron_variant	UMODL1	3e-08	Tier 4: intronic/intergenic
rs7873478	9	858429	T>C	0.05	intron_variant	DMRT1	3e-07	Tier 4: intronic/intergenic
rs6068020	20	51943113	T>A,C,G	0.49	intron_variant	RNU7-6P - ZFP64	5e-07	Tier 4: intronic/intergenic
rs10841496	12	20368720	C>A	0.42	5_prime_UTR_variant	PDE3A-AS1, PDE3A	5e-07	Tier 2: splice/UTR
rs9814870	3	95969999	A>G,T	0.15	intergenic_variant	MTHFD2P1 - HNRNPKP4	7e-07	Tier 4: intronic/intergenic
rs1399645	2	139390262	C>A,G,T	0.02	intergenic_variant	AHCYP4 - SNORA72	9e-07	Tier 4: intronic/intergenic
rs186420734	2	49429854	C>A	0.005	intron_variant	MIR548BAHG - RPL7P13	1e-06	Tier 4: intronic/intergenic
rs10848911	12	3705072	G>A,T	0.11	intron_variant	CRACR2A	4e-06	Tier 4: intronic/intergenic

ClinVar germline variants

182 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 41 pathogenic, 39 likely pathogenic, 22 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1244244	NM_000044.6(AR):c.2486A>T (p.Asp829Val)	AR	Pathogenic	criteria provided, single submitter
2572770	NM_000044.6(AR):c.2270A>G (p.Asn757Ser)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061774	NM_000044.6(AR):c.2059T>C (p.Cys687Arg)	AR	Pathogenic	criteria provided, single submitter
9823	NM_000044.6(AR):c.2567G>A (p.Arg856His)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870519	GRCh37/hg19 Yq11.221-11.23(chrY:18546605-28799937)x0	BPY2B	Pathogenic	criteria provided, single submitter
2674645	NM_024764.4(CATSPERB):c.2126G>A (p.Arg709Gln)	CATSPERB	Pathogenic	no assertion criteria provided
4526302	GRCh38/hg38 Yq11.222-12(chrY:18851940-57212132)x0	CDY1B	Pathogenic	criteria provided, single submitter
488651	NM_020384.4(CLDN2):c.481G>C (p.Gly161Arg)	CLDN2	Pathogenic	no assertion criteria provided
870522	GRCh37/hg19 Yq11.223-11.23(chrY:24651462-28328263)x0	DAZ3	Pathogenic	criteria provided, single submitter
870526	GRCh37/hg19 Yq11.222-11.23(chrY:21719615-28799937)x0	DAZ4	Pathogenic	criteria provided, single submitter
870525	GRCh37/hg19 Yq11.21-11.221(chrY:14443478-15230544)x0	DDX3Y	Pathogenic	criteria provided, single submitter
4526326	Single allele	DM1-AS	Pathogenic	criteria provided, single submitter
2582766	NM_173628.4(DNAH17):c.7752+2T>A	DNAH17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3388882	NM_173628.4(DNAH17):c.1076_1077dup (p.Lys360Ter)	DNAH17	Pathogenic	criteria provided, multiple submitters, no conflicts
220581	NM_001369.3(DNAH5):c.5557A>T (p.Lys1853Ter)	DNAH5	Pathogenic	criteria provided, multiple submitters, no conflicts
870521	GRCh37/hg19 Yq11.21-11.223(chrY:14495040-24070172)x0	EIF1AY	Pathogenic	criteria provided, single submitter
1684032	NM_003602.5(FKBP6):c.589-2A>G	FKBP6	Pathogenic	criteria provided, single submitter
1684033	NM_003602.5(FKBP6):c.508_529dup (p.Phe177fs)	FKBP6	Pathogenic	criteria provided, single submitter
3024514	NM_144594.3(GTSF1):c.221_222del (p.Arg74fs)	GPR84-AS1	Pathogenic	criteria provided, single submitter
1711131	NM_032132.5(HORMAD1):c.1021C>T (p.Gln341Ter)	HORMAD1	Pathogenic	criteria provided, single submitter
3061751	NM_001321739.2(M1AP):c.1073_1074+10del	M1AP	Pathogenic	criteria provided, single submitter
981142	NM_004959.5(NR5A1):c.1052C>T (p.Ala351Val)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, single submitter
3602633	Single allele	NXT2	Pathogenic	criteria provided, single submitter
812721	NM_018076.5(ODAD2):c.2097+1G>A	ODAD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2672266	NM_152401.3(PDCL2):c.128-1G>A	PDCL2	Pathogenic	no assertion criteria provided
870512	GRCh37/hg19 Yq11.222-11.23(chrY:20608554-28799937)x0	PRORY	Pathogenic	criteria provided, single submitter
870513	GRCh37/hg19 Yq11.223-11.23(chrY:24644460-28341390)x0	PRY	Pathogenic	criteria provided, single submitter
870527	GRCh37/hg19 Yq11.21-11.23(chrY:13800703-28799937)x0	PRY	Pathogenic	criteria provided, single submitter
870528	GRCh37/hg19 Yq11.221-11.23(chrY:15427283-28799937)x0	PRY2	Pathogenic	criteria provided, single submitter
870520	GRCh37/hg19 Yq11.222-11.23(chrY:20111978-28423925)x0	RBMY1A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 48 · 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
SEPTIN4	Strong	Autosomal recessive	male infertility
KATNAL2	Moderate	Autosomal recessive	male infertility	2
ACTL7A	Limited	Autosomal recessive	male infertility
ADAM20	Limited	Autosomal dominant	male infertility
DNAH3	Limited	Autosomal recessive	male infertility
MCM9	Limited	Autosomal recessive	male infertility	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCM9	Orphanet:444048	46,XX ovarian dysgenesis-short stature syndrome
SEPTIN4	Orphanet:171709	Male infertility due to globozoospermia
TEX11	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
BRWD1	Orphanet:244	Primary ciliary dyskinesia
ARL6	Orphanet:110	Bardet-Biedl syndrome
ARL6	Orphanet:791	Retinitis pigmentosa
USP26	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
SALL4	Orphanet:2307	IVIC syndrome
SALL4	Orphanet:233	Duane retraction syndrome
SALL4	Orphanet:261638	Okihiro syndrome due to 20q13 microdeletion
SALL4	Orphanet:261647	Okihiro syndrome due to a point mutation
SALL4	Orphanet:959	Acro-renal-ocular syndrome
DAZ3	Orphanet:1646	Chromosome Y microdeletion syndrome
DAZ4	Orphanet:1646	Chromosome Y microdeletion syndrome
CFAP52	Orphanet:101063	Situs inversus totalis
SYCP3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FKBP10	Orphanet:1149	Kuskokwim syndrome
FKBP10	Orphanet:216812	Osteogenesis imperfecta type 3
FKBP10	Orphanet:216820	Osteogenesis imperfecta type 4
FKBP10	Orphanet:2771	Bruck syndrome
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
TDRD9	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CLCA4	Orphanet:586	Cystic fibrosis
ZMYND15	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
PNLDC1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
ADCY10	Orphanet:2197	Idiopathic hypercalciuria
ODAD2	Orphanet:244	Primary ciliary dyskinesia
CCDC40	Orphanet:244	Primary ciliary dyskinesia
SHOC1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
DAZ1	Orphanet:1646	Chromosome Y microdeletion syndrome
DDX3Y	Orphanet:1646	Chromosome Y microdeletion syndrome
FBXO43	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
DMRT1	Orphanet:242	46,XY complete gonadal dysgenesis
DNAH10	Orphanet:137893	Male infertility due to large-headed multiflagellar polyploid spermatozoa
DNAH10	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
DNAH11	Orphanet:244	Primary ciliary dyskinesia
DNAH17	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
DNAH5	Orphanet:244	Primary ciliary dyskinesia
DNAH9	Orphanet:101063	Situs inversus totalis
DNAH9	Orphanet:157769	Situs ambiguus
DNAH9	Orphanet:244	Primary ciliary dyskinesia
DNAI1	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

75 cohort genes, 72 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3
multi_evidence	72

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTL7A	HGNC:161	ENSG00000187003	Q9Y615	Actin-like protein 7A	gencc
ADAM20	HGNC:199	ENSG00000134007	O43506	Disintegrin and metalloproteinase domain-containing protein 20	gencc
MCM9	HGNC:21484	ENSG00000111877	Q9NXL9	DNA helicase MCM9	gencc
KATNAL2	HGNC:25387	ENSG00000167216	Q8IYT4	Katanin p60 ATPase-containing subunit A-like 2	gencc
DNAH3	HGNC:2949	ENSG00000158486	Q8TD57	Dynein axonemal heavy chain 3	gencc
SEPTIN4	HGNC:9165	ENSG00000108387	O43236	Septin-4	gencc
TDRD1	HGNC:11712	ENSG00000095627	Q9BXT4	Tudor domain-containing protein 1	clinvar
TEX11	HGNC:11733	ENSG00000120498	Q8IYF3	Testis-expressed protein 11	clinvar
BRWD1	HGNC:12760	ENSG00000185658	Q9NSI6	Bromodomain and WD repeat-containing protein 1	clinvar
ARL6	HGNC:13210	ENSG00000113966	Q9H0F7	ADP-ribosylation factor-like protein 6	gwas
USP26	HGNC:13485	ENSG00000134588	Q9BXU7	Ubiquitin carboxyl-terminal hydrolase 26	clinvar
BPY2	HGNC:13508	ENSG00000183753	O14599	Testis-specific basic protein Y 2	clinvar
POF1B	HGNC:13711	ENSG00000124429	Q8WVV4	Protein POF1B	clinvar
PRY	HGNC:14024	ENSG00000169789	O14603	PTPN13-like protein, Y-linked	clinvar
ACTR5	HGNC:14671	ENSG00000101442	Q9H9F9	Actin-related protein 5	clinvar
SALL4	HGNC:15924	ENSG00000101115	Q9UJQ4	Sal-like protein 4	gwas
DAZ3	HGNC:15965	ENSG00000187191	Q9NR90	Deleted in azoospermia protein 3	clinvar
DAZ4	HGNC:15966	ENSG00000205916	Q86SG3	Deleted in azoospermia protein 4	clinvar
CFAP52	HGNC:16053	ENSG00000166596	Q8N1V2	Cilia- and flagella-associated protein 52	clinvar
CCT6A	HGNC:1620	ENSG00000146731	P40227	T-complex protein 1 subunit zeta	clinvar
CXCL16	HGNC:16642	ENSG00000161921	Q9H2A7	C-X-C motif chemokine 16	clinvar
PIWIL2	HGNC:17644	ENSG00000197181	Q8TC59	Piwi-like protein 2	clinvar
SYCP3	HGNC:18130	ENSG00000139351	Q8IZU3	Synaptonemal complex protein 3	clinvar
NXT2	HGNC:18151	ENSG00000101888	Q9NPJ8	NTF2-related export protein 2	clinvar
FKBP10	HGNC:18169	ENSG00000141756	Q96AY3	Peptidyl-prolyl cis-trans isomerase FKBP10	clinvar
ATP6V1C2	HGNC:18264	ENSG00000143882	Q8NEY4	V-type proton ATPase subunit C 2	clinvar
FAM9A	HGNC:18403	ENSG00000183304	Q8IZU1	Protein FAM9A	clinvar
DDX4	HGNC:18700	ENSG00000152670	Q9NQI0	Probable ATP-dependent RNA helicase DDX4	clinvar
CATSPER2	HGNC:18810	ENSG00000166762	Q96P56	Cation channel sperm-associated protein 2	clinvar
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	clinvar
HIPK4	HGNC:19007	ENSG00000160396	Q8NE63	Homeodomain-interacting protein kinase 4	clinvar
TDRD9	HGNC:20122	ENSG00000156414	Q8NDG6	ATP-dependent RNA helicase TDRD9	clinvar
CLCA4	HGNC:2018	ENSG00000016602	Q14CN2	Calcium-activated chloride channel regulator 4	clinvar
CLDN2	HGNC:2041	ENSG00000165376	P57739	Claudin-2	clinvar
CATSPERB	HGNC:20500	ENSG00000133962	Q9H7T0	Cation channel sperm-associated auxiliary subunit beta	clinvar
ZMYND15	HGNC:20997	ENSG00000141497	Q9H091	Zinc finger MYND domain-containing protein 15	clinvar
PNLDC1	HGNC:21185	ENSG00000146453	Q8NA58	Poly(A)-specific ribonuclease PNLDC1	clinvar
ADCY10	HGNC:21285	ENSG00000143199	Q96PN6	Adenylate cyclase type 10	clinvar
PRY2	HGNC:21504	ENSG00000169807	O14603	PTPN13-like protein, Y-linked	clinvar
GALNTL5	HGNC:21725	ENSG00000106648	Q7Z4T8	Inactive polypeptide N-acetylgalactosaminyltransferase-like protein 5	clinvar
RBMY1E	HGNC:23916	ENSG00000242389	A6NEQ0	RNA-binding motif protein, Y chromosome, family 1 member E	clinvar
CDY1B	HGNC:23920	ENSG00000172352	Q9Y6F8	Testis-specific chromodomain protein Y 1	clinvar
C1orf146	HGNC:24032	ENSG00000203910	Q5VVC0	Protein SPO16 homolog	clinvar
ANKS1B	HGNC:24600	ENSG00000185046	Q7Z6G8	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	clinvar
TDRD12	HGNC:25044	ENSG00000173809	Q587J7	Putative ATP-dependent RNA helicase TDRD12	clinvar
HAUS1	HGNC:25174	ENSG00000152240	Q96CS2	HAUS augmin-like complex subunit 1	clinvar
M1AP	HGNC:25183	ENSG00000159374	Q8TC57	Meiosis 1 arrest protein	clinvar
HORMAD1	HGNC:25245	ENSG00000143452	Q86X24	HORMA domain-containing protein 1	clinvar
BPY2B	HGNC:25449	ENSG00000183795	O14599	Testis-specific basic protein Y 2	clinvar
ODAD2	HGNC:25583	ENSG00000169126	Q5T2S8	Outer dynein arm-docking complex subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTL7A	Actin-like protein 7A	Essential for normal spermatogenesis and male fertility.
ADAM20	Disintegrin and metalloproteinase domain-containing protein 20	May be involved in sperm maturation and/or fertilization.
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).
KATNAL2	Katanin p60 ATPase-containing subunit A-like 2	Severs microtubules in vitro in an ATP-dependent manner.
DNAH3	Dynein axonemal heavy chain 3	Force generating protein of respiratory cilia.
SEPTIN4	Septin-4	Filament-forming cytoskeletal GTPase.
TDRD1	Tudor domain-containing protein 1	Plays a central role during spermatogenesis by participating in the repression transposable elements and preventing their mobilization, which is essential for the germline integrity.
TEX11	Testis-expressed protein 11	Regulator of crossing-over during meiosis.
BRWD1	Bromodomain and WD repeat-containing protein 1	May be a transcriptional activator.
ARL6	ADP-ribosylation factor-like protein 6	Involved in membrane protein trafficking at the base of the ciliary organelle.
USP26	Ubiquitin carboxyl-terminal hydrolase 26	Deubiquitinase regulating several biological processes through the deubiquitination of components of these processes.
POF1B	Protein POF1B	Plays a key role in the organization of epithelial monolayers by regulating the actin cytoskeleton.
ACTR5	Actin-related protein 5	Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
SALL4	Sal-like protein 4	Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.
DAZ3	Deleted in azoospermia protein 3	RNA-binding protein that plays an essential role in spermatogenesis.
DAZ4	Deleted in azoospermia protein 4	RNA-binding protein that plays an essential role in spermatogenesis.
CFAP52	Cilia- and flagella-associated protein 52	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme.
CCT6A	T-complex protein 1 subunit zeta	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis.
CXCL16	C-X-C motif chemokine 16	Acts as a scavenger receptor on macrophages, which specifically binds to OxLDL (oxidized low density lipoprotein), suggesting that it may be involved in pathophysiology such as atherogenesis.
PIWIL2	Piwi-like protein 2	Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.
SYCP3	Synaptonemal complex protein 3	Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase.
NXT2	NTF2-related export protein 2	Regulator of protein export for NES-containing proteins.
FKBP10	Peptidyl-prolyl cis-trans isomerase FKBP10	PPIases accelerate the folding of proteins during protein synthesis.
ATP6V1C2	V-type proton ATPase subunit C 2	Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
DDX4	Probable ATP-dependent RNA helicase DDX4	ATP-dependent RNA helicase required during spermatogenesis.
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.
HIPK4	Homeodomain-interacting protein kinase 4	Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter.
TDRD9	ATP-dependent RNA helicase TDRD9	ATP-binding RNA helicase required during spermatogenesis.
CLCA4	Calcium-activated chloride channel regulator 4	May be involved in mediating calcium-activated chloride conductance.
CLDN2	Claudin-2	Forms paracellular channels: polymerizes in tight junction strands with cation- and water-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.
CATSPERB	Cation channel sperm-associated auxiliary subunit beta	Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation.
ZMYND15	Zinc finger MYND domain-containing protein 15	Acts as a transcriptional repressor through interaction with histone deacetylases (HDACs).
PNLDC1	Poly(A)-specific ribonuclease PNLDC1	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.
ADCY10	Adenylate cyclase type 10	Catalyzes the formation of the signaling molecule cAMP.
GALNTL5	Inactive polypeptide N-acetylgalactosaminyltransferase-like protein 5	Probable inactive glycosyltransferase required during spermatid development.
RBMY1E	RNA-binding motif protein, Y chromosome, family 1 member E	RNA-binding protein which may be involved in spermatogenesis.
CDY1B	Testis-specific chromodomain protein Y 1	Has histone acetyltransferase activity, with a preference for histone H4.
C1orf146	Protein SPO16 homolog	Plays a key role in reinforcing the integrity of the central element of the synaptonemal complex (SC) thereby stabilizing SC, ensuring progression of meiotic prophase I in male and female germ cells.
ANKS1B	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	Isoform 2 may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells.
TDRD12	Putative ATP-dependent RNA helicase TDRD12	Probable ATP-binding RNA helicase required during spermatogenesis to repress transposable elements and preventing their mobilization, which is essential for the germline integrity.
HAUS1	HAUS augmin-like complex subunit 1	Contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex.
M1AP	Meiosis 1 arrest protein	Required for meiosis I progression during spermatogenesis.
HORMAD1	HORMA domain-containing protein 1	Plays a key role in meiotic progression.
ODAD2	Outer dynein arm-docking complex subunit 2	Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule.
MAEL	Protein maelstrom homolog	Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.
CCDC40	Coiled-coil domain-containing protein 40	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.
HENMT1	Small RNA 2’-O-methyltransferase	Methyltransferase that adds a 2’-O-methyl group at the 3’-end of piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence element…
SHOC1	Protein shortage in chiasmata 1 ortholog	ATPase required during meiosis for the formation of crossover recombination intermediates.
AXDND1	Axonemal dynein light chain domain-containing protein 1	May be essential for spermiogenesis and male fertility probably by regulating the manchette dynamics, spermatid head shaping and sperm flagellum assembly.

Protein-family classification

Druggable: 14 · Difficult: 8 · Unknown: 53 · Druggable fraction: 0.19

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
Other/Unknown	53	1.3×	0.053
Ion channel	1	1.5×	0.942
Enzyme (other)	7	1.1×	0.942
Transporter	1	1.0×	0.942
Protease	2	1.0×	0.942
Scaffold/PPI	4	0.9×	0.942
Antibody/Immunoglobulin	2	0.8×	0.942
Transcription factor	4	0.4×	0.985
Kinase	1	0.4×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTL7A	Other/Unknown	no		Actin, ACTL7A_N, ATPase_NBD
ADAM20	Protease	yes		Peptidase_M12B, Disintegrin_dom, Peptidase_M12B_N
MCM9	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
KATNAL2	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, LisH
DNAH3	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dhc_linker
SEPTIN4	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
TDRD1	Transcription factor	no		Znf_MYND, Tudor, SNase_OB-fold_sf
TEX11	Other/Unknown	no		TPR-like_helical_dom_sf, Spo22/ZIP4/TEX11, TPR_rpt
BRWD1	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
ARL6	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF
USP26	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
BPY2	Other/Unknown	no
POF1B	Other/Unknown	no		POF1B, POF1B_HlH
PRY	Other/Unknown	no
ACTR5	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD
SALL4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
DAZ3	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
DAZ4	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
CFAP52	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
CCT6A	Enzyme (other)	yes	3.6.4.B10	Chaperonin_TCP-1_CS, Cpn60/GroEL/TCP-1, Chap_CCT_zeta
CXCL16	Other/Unknown	no		CXCL16, CXCL16_dom
PIWIL2	Other/Unknown	no		PAZ_dom, Piwi, RNaseH-like_sf
SYCP3	Other/Unknown	no		XLR/SYCP3/FAM9_dom, XLR/SYCP3
NXT2	Other/Unknown	no		NTF2_dom, Nuclear_transport_factor_2_euk, NTF2-like_dom_sf
FKBP10	Other/Unknown	no		PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair
ATP6V1C2	Other/Unknown	no		ATPase_V1-cplx_csu, Vac_ATP_synth_c_sf
FAM9A	Other/Unknown	no		XLR/SYCP3
DDX4	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_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
HIPK4	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TDRD9	Other/Unknown	no		Helicase_C-like, Tudor, Helicase-assoc_dom
CLCA4	Antibody/Immunoglobulin	yes		VWF_A, CLCA_chordata, CLCA_N
CLDN2	Other/Unknown	no		PMP22/EMP/MP20/Claudin, Claudin2, Claudin
CATSPERB	Antibody/Immunoglobulin	yes		CATSPERB, CATSPERB_N, CATSPERB_2nd
ZMYND15	Transcription factor	no		Znf_MYND, ZMY15, Mss51-like_C
PNLDC1	Enzyme (other)	yes	3.1.13.4	RNase_CAF1, RNaseH-like_sf, RNaseH_sf
ADCY10	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adenylate_cyclase_typ10, P-loop_NTPase
PRY2	Other/Unknown	no
GALNTL5	Enzyme (other)	yes	2.4.1.41	Glyco_trans_2-like, Nucleotide-diphossugar_trans, GalNAc-T
RBMY1E	Other/Unknown	no		RRM_dom, RBM1CTR, Nucleotide-bd_a/b_plait_sf
CDY1B	Other/Unknown	no		Chromo/chromo_shadow_dom, Enoyl-CoA_hydra/iso, Enoyl-CoA_hydra_C
C1orf146	Other/Unknown	no		SCRE
ANKS1B	Scaffold/PPI	no		SAM, Ankyrin_rpt, PTB/PI_dom
TDRD12	Other/Unknown	no		Tudor, DEAD/DEAH_box_helicase_dom, P-loop_NTPase
HAUS1	Other/Unknown	no		HAUS1
M1AP	Other/Unknown	no		M1AP
HORMAD1	Other/Unknown	no		HORMA_dom, HORMA_dom_sf, HORMA_MeioticProgression
BPY2B	Other/Unknown	no
ODAD2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	2
moderate (6-20)	8
broad (>20)	65
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right testis	24
male germ line stem cell (sensu Vertebrata) in testis	20
left testis	18
primordial germ cell in gonad	17
secondary oocyte	11
testis	9
sperm	9
bronchial epithelial cell	9
right uterine tube	8
oocyte	7
cortical plate	6
male germ cell	4
bronchus	4
ventricular zone	4
epithelium of bronchus	3
right hemisphere of cerebellum	3
oviduct epithelium	3
buccal mucosa cell	3
colonic epithelium	3
gall bladder	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTL7A	62	tissue_specific	marker	left testis, right testis, testis
ADAM20	49	tissue_specific	yes	sperm, male germ cell, primordial germ cell in gonad
MCM9	233	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis
KATNAL2	175	ubiquitous	marker	right uterine tube, left lobe of thyroid gland, thyroid gland
DNAH3	156	tissue_specific	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
SEPTIN4	225	broad	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere
TDRD1	108	broad	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, oocyte
TEX11	68	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad
BRWD1	266	ubiquitous	marker	cortical plate, sural nerve, calcaneal tendon
ARL6	228	ubiquitous	marker	oviduct epithelium, Brodmann (1909) area 23, endothelial cell
USP26	62	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, buccal mucosa cell
BPY2	17		yes	left testis, testis, right testis
POF1B	176	broad	marker	upper arm skin, skin of leg, skin of abdomen
PRY	5		yes	colonic epithelium, ventricular zone, cortical plate
ACTR5	241	ubiquitous	yes	hair follicle, tongue squamous epithelium, olfactory bulb
SALL4	150	broad	marker	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis
DAZ3	6		yes	primordial germ cell in gonad, colonic epithelium, ventricular zone
DAZ4	16		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, right testis
CFAP52	170	tissue_specific	marker	bronchial epithelial cell, right uterine tube, bronchus
CCT6A	295	ubiquitous	marker	primordial germ cell in gonad, cortical plate, ganglionic eminence
CXCL16	237	ubiquitous	marker	left testis, right testis, gall bladder
PIWIL2	183	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, buccal mucosa cell
SYCP3	170	tissue_specific	marker	right testis, left testis, secondary oocyte
NXT2	273	ubiquitous	marker	hair follicle, oocyte, secondary oocyte
FKBP10	179	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta
ATP6V1C2	181	broad	marker	skin of abdomen, skin of leg, lower esophagus mucosa
FAM9A	20		marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
DDX4	113	tissue_specific	marker	secondary oocyte, right testis, sperm
CATSPER2	220	tissue_specific	yes	cerebellar vermis, right hemisphere of cerebellum, cerebellar cortex
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas

Protein interactions among cohort

Intra-cohort edges: 87.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
CCT6A	6,034
KATNAL2	5,866
FKBP10	3,473
DDX4	3,472
DDX3Y	3,194
BRWD1	2,695
EIF1AY	2,483
TDRD12	2,451
ANKS1B	2,428

Intra-cohort edges

A	B	Sources
ACTL7A	CFTR	intact
BPY2	CDY1B	string_interaction
BPY2	DAZ1	string_interaction
BPY2	DDX3Y	string_interaction
BPY2	PRY2	string_interaction
BPY2B	CDY1B	string_interaction
BPY2B	DAZ1	string_interaction
BPY2B	DDX3Y	string_interaction
BPY2B	EIF1AY	string_interaction
BPY2B	PRY	string_interaction
BPY2B	PRY2	string_interaction
C1orf146	SHOC1	string_interaction
C1orf146	TEX11	string_interaction
CATSPER2	CATSPERB	string_interaction
CCDC40	DNAH11	string_interaction
CCDC40	DNAH3	string_interaction
CCDC40	DNAH5	string_interaction
CCDC40	DNAH9	string_interaction
CCDC40	DNAI1	string_interaction
CCDC40	ODAD2	string_interaction
CCT6A	CFAP52	biogrid_interaction
CDY1B	DAZ1	string_interaction
CDY1B	DDX3Y	string_interaction
CDY1B	PRY	string_interaction
CDY1B	PRY2	string_interaction
CFAP52	CFTR	intact
CFTR	CLCA4	string_interaction
CFTR	DAZ3	intact
CFTR	DAZ4	intact
CFTR	KATNAL2	intact
CFTR	POF1B	intact
CFTR	USP26	intact
DAZ1	DDX3Y	string_interaction
DAZ1	DDX4	string_interaction
DAZ1	PRY	string_interaction
DAZ1	PRY2	string_interaction
DDX3Y	EIF1AY	string_interaction
DDX3Y	PRY	string_interaction
DDX3Y	PRY2	string_interaction
DDX4	MAEL	string_interaction
DDX4	PIWIL2	string_interaction
DDX4	SYCP3	string_interaction
DDX4	TDRD1	string_interaction
DMRT1	SOX30	string_interaction
DNAH10	DNAH5	biogrid_interaction
DNAH10	DNAI1	string_interaction
DNAH11	DNAH17	biogrid_interaction
DNAH11	DNAI1	string_interaction
DNAH11	ODAD2	string_interaction
DNAH3	DNAI1	string_interaction

Structural data

PDB: 33 · AlphaFold-only: 41 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCT6A	P40227	65
CFTR	P13569	58
ADCY10	Q96PN6	37
SALL4	Q9UJQ4	13
MCM9	Q9NXL9	6
ACTR5	Q9H9F9	6
ANKS1B	Q7Z6G8	4
PIWIL2	Q8TC59	3
CFAP52	Q8N1V2	2
CDY1B	Q9Y6F8	2
HENMT1	Q5T8I9	2
PLD6	Q8N2A8	2
ACTL7A	Q9Y615	1
DNAH3	Q8TD57	1
SEPTIN4	O43236	1
TDRD1	Q9BXT4	1
BRWD1	Q9NSI6	1
ARL6	Q9H0F7	1
POF1B	Q8WVV4	1
SYCP3	Q8IZU3	1
CLDN2	P57739	1
HAUS1	Q96CS2	1
HORMAD1	Q86X24	1
ODAD2	Q5T2S8	1
MAEL	Q96JY0	1
CCDC40	Q4G0X9	1
CRACR2A	Q9BSW2	1
DMRT1	Q9Y5R6	1
DNAH5	Q8TE73	1
PDCL2	Q8N4E4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NXT2	Q9NPJ8	94.35
PNLDC1	Q8NA58	90.16
CLCA4	Q14CN2	89.48
FKBP10	Q96AY3	89.19
TEX11	Q8IYF3	86.45
ATP6V1C2	Q8NEY4	86.29
C1orf146	Q5VVC0	86.23
GALNTL5	Q7Z4T8	85.63
CATSPERB	Q9H7T0	84.99
ADAM20	O43506	83.06
TDRD9	Q8NDG6	80.45
GPAT2	Q6NUI2	78.38
EIF1AY	O14602	77.59
M1AP	Q8TC57	74.03
TDRD12	Q587J7	73.57
ZMYND15	Q9H091	72.98
DDX3Y	O15523	72.91
KATNAL2	Q8IYT4	72.21
AXDND1	Q5T1B0	70.90
HIPK4	Q8NE63	70.45
CT45A1	Q5HYN5	69.95
CATSPER2	Q96P56	69.83
DDX4	Q9NQI0	69.06
FAM9A	Q8IZU1	66.59
CXCL16	Q9H2A7	65.77
ANTXRL	A6NF34	63.17
DAZ3	Q9NR90	61.94
USP26	Q9BXU7	60.28
DAZ4	Q86SG3	57.51
DAZ1	Q9NQZ3	57.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 153. Enrichment computed across 98 evidence-associated genes (41 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 41 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PIWI-interacting RNA (piRNA) biogenesis	11	105.7×	1e-18	TDRD1, PIWIL2, DDX4, TDRD9, TDRD12, MAEL, HENMT1, PLD6 (+3 more)
Gene Silencing by RNA	5	43.5×	7e-06	TDRD1, TDRD9, TDRD12, MAEL, MOV10L1
Sperm Motility And Taxes	2	61.9×	0.023	CATSPER2, CATSPERB
RHOBTB GTPase Cycle	2	39.8×	0.043	CCT6A, MYO6
Transcriptional regulation of testis differentiation	2	34.8×	0.045	DMRT1, NR5A1
Transcriptional regulation of pluripotent stem cells	2	26.5×	0.064	SALL4, NR5A1
RHOBTB2 GTPase cycle	2	23.2×	0.072	CCT6A, MYO6
SUMOylation of intracellular receptors	2	16.4×	0.121	AR, NR5A1
Gene expression (Transcription)	7	3.0×	0.121	TDRD1, TDRD9, TDRD12, MAEL, AR, MOV10L1, NR5A1
Synthesis of PA	2	14.3×	0.131	GPAT2, PLD6
RHO GTPases regulate CFTR trafficking	1	92.8×	0.149	CFTR
Signaling by Overexpressed Wild-Type EGFR in Cancer	1	69.6×	0.182	AREG
Nuclear Receptor transcription pathway	2	9.8×	0.209	AR, NR5A1
Release of apoptotic factors from the mitochondria	1	39.8×	0.212	SEPTIN4
SMAC, XIAP-regulated apoptotic response	1	39.8×	0.212	SEPTIN4
Synthesis of PG	1	30.9×	0.212	PLD6
Inhibition of Signaling by Overexpressed EGFR	1	30.9×	0.212	AREG
Interleukin-9 signaling	1	30.9×	0.212	IL9R
Signaling by EGFR in Cancer	1	27.9×	0.212	AREG
EGFR interacts with phospholipase C-gamma	1	27.9×	0.212	AREG
Folding of actin by CCT/TriC	1	27.9×	0.212	CCT6A
Interaction With Cumulus Cells And The Zona Pellucida	1	25.3×	0.212	ADAM20
Fertilization	1	23.2×	0.212	ADAM20
Gap junction degradation	1	23.2×	0.212	MYO6
NFE2L2 regulating tumorigenic genes	1	23.2×	0.212	AREG
Reproduction	2	9.3×	0.212	SYCP3, ADAM20
SUMO E3 ligases SUMOylate target proteins	2	8.7×	0.212	AR, NR5A1
SUMOylation	2	8.0×	0.212	AR, NR5A1
Meiotic synapsis	2	6.9×	0.212	SYCP3, FKBP6
Deubiquitination	2	6.1×	0.212	ACTR5, AR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 87 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
piRNA processing	13	125.9×	2e-23	TDRD1, PIWIL2, DDX4, TDRD9, PNLDC1, TDRD12, MAEL, HENMT1 (+5 more)
spermatogenesis	23	9.3×	4e-14	TDRD1, USP26, BPY2, DAZ3, DAZ4, PIWIL2, DDX4, TDRD9 (+15 more)
transposable element silencing by piRNA-mediated DNA methylation	8	103.3×	3e-13	TDRD1, PIWIL2, DDX4, TDRD9, TDRD12, MAEL, FKBP6, MOV10L1
spermatid development	11	18.4×	2e-09	CFAP52, ACTL7A, SYCP3, FAM9A, ZMYND15, ADCY10, GALNTL5, PDCL2 (+3 more)
meiotic cell cycle	9	25.3×	6e-09	TDRD1, PIWIL2, SYCP3, FAM9A, HORMAD1, FBXO43, PLD6, FKBP6 (+1 more)
cilium movement involved in cell motility	6	46.5×	2e-07	DNAH10, DNAH11, DNAH17, DNAH3, DNAH5, DNAH9
transposable element silencing by piRNA-mediated heterochromatin formation	4	155.0×	2e-07	PIWIL2, DDX4, TDRD9, PIWIL1
fertilization	7	25.1×	6e-07	TEX11, ACTL7A, CATSPER2, TDRD9, TDRD12, MAEL, KLK14
flagellated sperm motility	8	10.8×	4e-05	CFAP52, DDX4, CATSPER2, CCDC40, DNAH11, DNAH5, DNAI1, SEPTIN4
cilium movement	5	22.5×	1e-04	ODAD2, CCDC40, DNAH5, DNAH9, DNAI1
epithelial cilium movement involved in extracellular fluid movement	4	35.2×	2e-04	ADCY10, CCDC40, DNAH5, DNAI1
outer dynein arm assembly	4	33.7×	2e-04	ODAD2, DNAH17, DNAH5, DNAI1
regulation of cilium beat frequency	3	72.6×	2e-04	ODAD2, CCDC40, DNAH11
regulatory ncRNA-mediated gene silencing	4	31.0×	2e-04	PIWIL2, MAEL, FKBP6, PIWIL1
single fertilization	6	12.6×	2e-04	BPY2, CFAP52, ACTL7A, ADAM20, BPY2B, AR
synaptonemal complex assembly	4	29.8×	2e-04	TEX11, C1orf146, HORMAD1, SHOC1
male meiosis I	4	26.7×	3e-04	SYCP3, DDX4, TDRD9, MOV10L1
male meiotic nuclear division	4	25.0×	4e-04	DDX4, TDRD9, TDRD12, MAEL
determination of left/right symmetry	5	14.7×	5e-04	ARL6, ODAD2, DNAH11, DNAH5, DNAI1
positive regulation of meiosis I	2	193.7×	5e-04	PIWIL2, DMRT1
positive regulation of translational initiation	3	29.1×	0.003	DAZ3, DAZ4, DAZ1
morphogenesis of an epithelial fold	2	96.8×	0.003	HOXD13, AR
piRNA-mediated gene silencing by mRNA destabilization	2	96.8×	0.003	PIWIL2, PIWIL1
3’-UTR-mediated mRNA stabilization	3	24.2×	0.004	DAZ3, DAZ4, DAZ1
P granule organization	2	64.6×	0.006	TDRD1, PLD6
reciprocal meiotic recombination	3	19.4×	0.008	TEX11, C1orf146, SHOC1
meiosis I	2	55.3×	0.008	M1AP, DMRT1
negative regulation of meiotic nuclear division	2	48.4×	0.011	FBXO43, DMRT1
negative regulation of developmental process	2	43.0×	0.013	TEX11, MAEL
germ cell development	3	15.7×	0.013	TDRD1, DDX4, MOV10L1

Therapeutics

Drugs indicated for this disease

1 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Follitropin	Approved (phase 4)
Folic Acid	Phase 3 (in late-stage trials)
Probenecid	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Urofollitropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cholecalciferol, Denosumab, Follitropin Alfa, Letrozole, Tamoxifen, Vitamin E.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 72

Druggability breadth: 19 of 98 evidence-associated genes (19%) 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
HIPK4	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIPK4	37	4
CFTR	14	4
ACTR5	1	2
ACTL7A	0	0
ADAM20	0	0
MCM9	0	0
KATNAL2	0	0
DNAH3	0	0
SEPTIN4	0	0
TDRD1	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
AFATINIB	4	HIPK4
FEDRATINIB	4	HIPK4
SORAFENIB	4	HIPK4
NERATINIB	4	HIPK4
AFATINIB DIMALEATE	4	HIPK4
BOSUTINIB	4	HIPK4
NINTEDANIB	4	HIPK4
SUNITINIB	4	HIPK4
ERLOTINIB	4	HIPK4
QUIZARTINIB	4	HIPK4
CRIZOTINIB	4	HIPK4
MIDOSTAURIN	4	HIPK4
GEFITINIB	4	HIPK4
IMATINIB	4	HIPK4
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
LINIFANIB	3	HIPK4
ENZASTAURIN	3	HIPK4
CANERTINIB	3	HIPK4
ALVOCIDIB	3	HIPK4
LESTAURTINIB	3	HIPK4
RUBOXISTAURIN	3	HIPK4
MOLIBRESIB	2	ACTR5
GALICAFTOR	2	CFTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1
HIPK4	211	Binding:210, Functional:1
BRWD1	37	Binding:37
ADCY10	14	Binding:14
SALL4	12	Binding:12
ACTR5	7	Binding:7
CDY1B	4	Binding:4
KATNAL2	1	Binding:1
POF1B	1	Binding:1
CCT6A	1	Binding:1
CRACR2A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CCT6A	3.6.4.B10
DDX4	3.6.4.13	RNA helicase
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase
PNLDC1	3.1.13.4	poly(A)-specific ribonuclease
ADCY10	4.6.1.1	adenylate cyclase
GALNTL5	2.4.1.41	polypeptide N-acetylgalactosaminyltransferase
DDX3Y	3.6.4.13	RNA helicase
GPAT2	2.3.1.15	glycerol-3-phosphate 1-O-acyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CFTR	520
HIPK4	211

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; 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
AFATINIB	4	HIPK4
FEDRATINIB	4	HIPK4
SORAFENIB	4	HIPK4
NERATINIB	4	HIPK4
AFATINIB DIMALEATE	4	HIPK4
BOSUTINIB	4	HIPK4
NINTEDANIB	4	HIPK4
SUNITINIB	4	HIPK4
ERLOTINIB	4	HIPK4
QUIZARTINIB	4	HIPK4
CRIZOTINIB	4	HIPK4
MIDOSTAURIN	4	HIPK4
GEFITINIB	4	HIPK4
IMATINIB	4	HIPK4
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
LINIFANIB	3	HIPK4
ENZASTAURIN	3	HIPK4
CANERTINIB	3	HIPK4
ALVOCIDIB	3	HIPK4
LESTAURTINIB	3	HIPK4
RUBOXISTAURIN	3	HIPK4
MOLIBRESIB	2	ACTR5
GALICAFTOR	2	CFTR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CFTR, HIPK4
B	Phased (≥1) drug, not yet approved	1	ACTR5
C	Druggable family + PDB, no drug	2	CCT6A, ADCY10
D	Druggable family + AlphaFold only, no drug	10	ADAM20, USP26, DDX4, CATSPER2, CLCA4, CATSPERB, PNLDC1, GALNTL5, DDX3Y, GPAT2
E	Difficult family or no structure, no drug	60	ACTL7A, MCM9, KATNAL2, DNAH3, SEPTIN4, TDRD1, TEX11, BRWD1, ARL6, BPY2 (+50 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DAZ3	0	CFTR
DAZ4	0	CFTR
CLCA4	0	CFTR
ACTL7A	0	—
ADAM20	0	—
MCM9	0	—
KATNAL2	1	—
DNAH3	0	—
SEPTIN4	0	—
TDRD1	0	—
TEX11	0	—
BRWD1	37	—
ARL6	0	—
USP26	0	—
BPY2	0	—
POF1B	1	—
PRY	0	—
SALL4	12	—
CFAP52	0	—
CCT6A	1	—
CXCL16	0	—
PIWIL2	0	—
SYCP3	0	—
NXT2	0	—
FKBP10	0	—
ATP6V1C2	0	—
FAM9A	0	—
DDX4	0	—
CATSPER2	0	—
TDRD9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 125.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	98
PHASE2	6
PHASE4	5
PHASE3	5
PHASE2/PHASE3	4
PHASE1	3
EARLY_PHASE1	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT04704141	Not specified	NOT_YET_RECRUITING	Relationship of the Microenvironment and Male Fertility
NCT04959864	Not specified	RECRUITING	Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation
NCT05479474	Not specified	RECRUITING	Platelet Rich Plasma Testis Treatment for Infertile Men
NCT05966883	Not specified	ACTIVE_NOT_RECRUITING	SpermQT Prospective Observational Trial
NCT06193850	Not specified	RECRUITING	Protocol N. 2014 - Observational Study on the Quality of Life of Outpatients
NCT06324071	Not specified	RECRUITING	Study to Verify the Efficacy of a Product Containing 125 mg of TetraSOD® for the Treatment of Male Infertility
NCT06561451	Not specified	RECRUITING	Live Birth Rate Between ICSI and AOA and ICSI Alone in Patients With Severe Teratospermia
NCT06566599	Not specified	ACTIVE_NOT_RECRUITING	Preimplantation Genetic Testing for Aneuploidy (PGT-A) in Couples With Non-obstructive Azoospermia (NOA)
NCT06742437	Not specified	RECRUITING	Efficacy and Safety of a New Sperm Capacitation Method
NCT06880302	Not specified	RECRUITING	Male Infertility and Assisted Reproductive Technologies Research Biobank
NCT06956287	Not specified	RECRUITING	The Efficiency of a New Sperm-Wash Device for Intrauterine Insemination in Couples With Infertility
NCT06974175	Not specified	NOT_YET_RECRUITING	Effect of Graminex on Infertility Related to Male Accessory Glands Inflammation
NCT07056400	Not specified	ACTIVE_NOT_RECRUITING	Trial to Improve Fertilization Rate and Embryo Development in Intracytoplasmic Sperm Injection (ICSI) Cycles

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLOMIPHENE	4	4
ALITRETINOIN	4	1
ARTENIMOL	4	1
BETA CAROTENE	4	1
BETAINE	4	1
BUPIVACAINE	4	1
CALCITRIOL	4	1
CALCIUM	4	1
DACLATASVIR	4	1
FOLIC ACID	4	1
FOLLITROPIN ALFA	4	1
ISOTRETINOIN	4	1
LEVOCARNITINE	4	1
SIMEPREVIR	4	1
SOFOSBUVIR	4	1
UROFOLLITROPIN	4	1
VITAMIN E	4	1
ENCLOMIPHENE CITRATE	3	2
DOCONEXENT	3	1
SELENIUM	3	1
UBIDECARENONE	3	1
ZINC ION	3	1
CHEMBL5072826	0	1
CHEMBL1258950	0	1
CHEMBL1259058	0	1
CHEMBL4287268	0	1
CHEMBL4442791	0	1
CHEMBL4634610	0	1
CHEMBL4761872	0	1
CHEMBL5094734	0	1