Azoospermia

Summary

Azoospermia (MONDO:0100459) is a disease caused by DMC1 (GenCC Strong), with 22 cohort genes and 27 clinical trials. The dominant Reactome pathway is PIWI-interacting RNA (piRNA) biogenesis (4 cohort genes). Top therapeutic interventions include menotropins and urofollitropin.

At a glance

• Causal gene: DMC1 (GenCC Strong)
• Cohort genes: 22
• ClinVar variants: 24
• Clinical trials: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	azoospermia
Mondo ID	MONDO:0100459
MeSH	D053713
DOID	DOID:14227
ICD-10-CM	N46.0
ICD-11	532688254
SNOMED CT	425558002
UMLS	C0004509
MedGen	2150
Is cancer (heuristic)	no

Data availability: 24 ClinVar variants · 3 GenCC gene-disease records · 29 cell lines.

Disease family

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

Related subtypes (7): 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, oligoasthenoteratozoospermia

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

24 retrieved; paginated sample, class counts are floors:

19 pathogenic, 2 likely pathogenic, 2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267800	46;XY;t(7;8)(p12.3;p11.2)dn		Pathogenic	criteria provided, single submitter
992822	NM_174978.3(C14orf39):c.204_205del (p.His68fs)	C14orf39	Pathogenic	no assertion criteria provided
1328946	NM_013264.5(DDX25):c.1129C>T (p.Arg377Ter)	DDX25	Pathogenic	no assertion criteria provided
1328944	NM_007068.4(DMC1):c.364A>G (p.Thr122Ala)	DMC1	Pathogenic	no assertion criteria provided
1328945	NM_007068.4(DMC1):c.860C>A (p.Pro287His)	DMC1	Pathogenic	no assertion criteria provided
526381	NM_020937.4(FANCM):c.5791C>T (p.Arg1931Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328948	NM_052957.5(GCNA):c.1507del (p.Glu504fs)	GCNA	Pathogenic	no assertion criteria provided
1328955	NM_001102592.2(HENMT1):c.226G>A (p.Gly76Arg)	HENMT1	Pathogenic	no assertion criteria provided
1328956	NM_001102592.2(HENMT1):c.456C>G (p.Tyr152Ter)	HENMT1	Pathogenic	no assertion criteria provided
1328943	NM_001017975.6(HFM1):c.3588+1G>A	HFM1	Pathogenic	no assertion criteria provided
1328949	NM_144688.5(KASH5):c.1146+5G>A	KASH5	Pathogenic	no assertion criteria provided
1328953	NM_173518.5(MCMDC2):c.1795C>T (p.Arg599Ter)	MCMDC2	Pathogenic	no assertion criteria provided
1328958	NM_001163560.3(MEIOB):c.1118_1121del (p.Phe373fs)	MEIOB	Pathogenic	no assertion criteria provided
1328947	NM_018995.3(MOV10L1):c.743+5G>A	MOV10L1	Pathogenic	no assertion criteria provided
1328951	NM_172166.4(MSH5):c.537+1G>A	MSH5	Pathogenic	no assertion criteria provided
1328952	NM_001048205.2(REC8):c.860_861del (p.Pro287fs)	REC8	Pathogenic	no assertion criteria provided
1328950	NM_153046.3(TDRD9):c.3483_3484dup (p.Ser1162fs)	TDRD9	Pathogenic	no assertion criteria provided
560416	NM_153046.3(TDRD9):c.720_723del (p.Ser241fs)	TDRD9	Pathogenic	no assertion criteria provided
1328954	NM_001083965.2(TDRKH):c.1003A>T (p.Lys335Ter)	TDRKH	Pathogenic	no assertion criteria provided
1328957	NM_001136505.2(TERB1):c.733G>A (p.Gly245Arg)	TERB1	Pathogenic	no assertion criteria provided
1328959	NM_032485.6(MCM8):c.482A>C (p.His161Pro)	MCM8	Likely pathogenic	criteria provided, single submitter
446251	NM_005390.5(PDHA2):c.679A>G (p.Met227Val)	PDHA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
267936	46;XY;t(12;14)(q15;q13)mat		Uncertain significance	criteria provided, single submitter
2584547	GRCh38/hg38 Yq11.221-11.222(chrY:17454742-17459891)	CDY2B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 11 · 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
DMC1	Strong	Autosomal recessive	azoospermia	3
HID1	Strong	Autosomal recessive	azoospermia	6
DMRT1	Limited	Autosomal dominant	azoospermia	4
NPAS2	Limited	Autosomal recessive	azoospermia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DMRT1	Orphanet:242	46,XY complete gonadal dysgenesis
GCNA	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
TDRD9	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FANCM	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FANCM	Orphanet:84	Fanconi anemia
TERB1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
MEIOB	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
MOV10L1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
MSH5	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
PDHA2	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

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
HID1	HGNC:15736	ENSG00000167861	Q8IV36	Protein HID1	gencc,clinvar
DMC1	HGNC:2927	ENSG00000100206	Q14565	Meiotic recombination protein DMC1/LIM15 homolog	gencc,clinvar
DMRT1	HGNC:2934	ENSG00000137090	Q9Y5R6	Doublesex- and mab-3-related transcription factor 1	gencc
NPAS2	HGNC:7895	ENSG00000170485	Q99743	Neuronal PAS domain-containing protein 2	gencc
TDRKH	HGNC:11713	ENSG00000182134	Q9Y2W6	Tudor and KH domain-containing protein	clinvar
GCNA	HGNC:15805	ENSG00000147174	Q96QF7	Germ cell nuclear acidic protein	clinvar
MCM8	HGNC:16147	ENSG00000125885	Q9UJA3	DNA helicase MCM8	clinvar
REC8	HGNC:16879	ENSG00000100918	O95072	Meiotic recombination protein REC8 homolog	clinvar
DDX25	HGNC:18698	ENSG00000109832	Q9UHL0	ATP-dependent RNA helicase DDX25	clinvar
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	clinvar
TDRD9	HGNC:20122	ENSG00000156414	Q8NDG6	ATP-dependent RNA helicase TDRD9	clinvar
HFM1	HGNC:20193	ENSG00000162669	A2PYH4	Probable ATP-dependent DNA helicase HFM1	clinvar
FANCM	HGNC:23168	ENSG00000187790	Q8IYD8	Fanconi anemia group M protein	clinvar
CDY2B	HGNC:23921	ENSG00000129873	Q9Y6F7	Testis-specific chromodomain protein Y 2	clinvar
MCMDC2	HGNC:26368	ENSG00000178460	Q4G0Z9	Minichromosome maintenance domain-containing protein 2	clinvar
HENMT1	HGNC:26400	ENSG00000162639	Q5T8I9	Small RNA 2’-O-methyltransferase	clinvar
KASH5	HGNC:26520	ENSG00000161609	Q8N6L0	Protein KASH5	clinvar
TERB1	HGNC:26675	ENSG00000249961	Q8NA31	Telomere repeats-binding bouquet formation protein 1	clinvar
MEIOB	HGNC:28569	ENSG00000162039	Q8N635	Meiosis-specific with OB domain-containing protein	clinvar
MOV10L1	HGNC:7201	ENSG00000073146	Q9BXT6	RNA helicase Mov10l1	clinvar
MSH5	HGNC:7328	ENSG00000204410	O43196	MutS protein homolog 5	clinvar
PDHA2	HGNC:8807	ENSG00000163114	P29803	Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HID1	Protein HID1	May play an important role in the development of cancers in a broad range of tissues.
DMC1	Meiotic recombination protein DMC1/LIM15 homolog	Participates in meiotic recombination, specifically in homologous strand assimilation, which is required for the resolution of meiotic double-strand breaks.
DMRT1	Doublesex- and mab-3-related transcription factor 1	Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.
NPAS2	Neuronal PAS domain-containing protein 2	Transcriptional activator which forms a core component of the circadian clock.
TDRKH	Tudor and KH domain-containing protein	Participates in the primary piRNA biogenesis pathway and is required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for the germline integrity.
GCNA	Germ cell nuclear acidic protein	May play a role in DNA-protein cross-links (DPCs) clearance through a SUMO-dependent recruitment to sites of DPCs, ensuring the genomic stability by protecting germ cells and early embryos from various sources of damage.
MCM8	DNA helicase MCM8	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).
REC8	Meiotic recombination protein REC8 homolog	Required during meiosis for separation of sister chromatids and homologous chromosomes.
DDX25	ATP-dependent RNA helicase DDX25	ATP-dependent RNA helicase.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
TDRD9	ATP-dependent RNA helicase TDRD9	ATP-binding RNA helicase required during spermatogenesis.
HFM1	Probable ATP-dependent DNA helicase HFM1	Required for crossover formation and complete synapsis of homologous chromosomes during meiosis.
FANCM	Fanconi anemia group M protein	DNA-dependent ATPase component of the Fanconi anemia (FA) core complex.
CDY2B	Testis-specific chromodomain protein Y 2	May have histone acetyltransferase activity.
MCMDC2	Minichromosome maintenance domain-containing protein 2	Plays an important role in meiotic recombination and associated DNA double-strand break repair.
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…
KASH5	Protein KASH5	As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton.
TERB1	Telomere repeats-binding bouquet formation protein 1	Meiosis-specific telomere-associated protein involved in meiotic telomere attachment to the nucleus inner membrane, a crucial step for homologous pairing and synapsis.
MEIOB	Meiosis-specific with OB domain-containing protein	Single-stranded DNA-binding protein required for homologous recombination in meiosis I.
MOV10L1	RNA helicase Mov10l1	ATP-dependent RNA helicase required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for germline integrity.
MSH5	MutS protein homolog 5	Involved in DNA mismatch repair and meiotic recombination processes.
PDHA2	Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial	Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex in testis.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 18 · Druggable fraction: 0.05

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	18	1.5×	0.030
Transcription factor	3	1.1×	0.763
Enzyme (other)	1	0.6×	0.853

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HID1	Other/Unknown	no		HID1/Ecm30
DMC1	Transcription factor	no		AAA+_ATPase, DNA_repair_Rad51/TF_NusA_a-hlx, Dmc1
DMRT1	Other/Unknown	no		DM_DNA-bd, DMRT1-like, DMRT
NPAS2	Transcription factor	no		PAS, Nuc_translocat, PAC
TDRKH	Other/Unknown	no		Tudor, KH_dom, KH_dom_type_1
GCNA	Other/Unknown	no		SprT-like_domain
MCM8	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
REC8	Other/Unknown	no		Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C
DDX25	Enzyme (other)	yes	3.6.4.13	Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
C14orf39	Other/Unknown	no		SIX6OS1
TDRD9	Other/Unknown	no		Helicase_C-like, Tudor, Helicase-assoc_dom
HFM1	Other/Unknown	no		Helicase_C-like, Sec63-dom, DEAD/DEAH_box_helicase_dom
FANCM	Other/Unknown	no		Helicase_C-like, ERCC4_domain, RuvA_2-like
CDY2B	Other/Unknown	no		Chromo/chromo_shadow_dom, Enoyl-CoA_hydra/iso, Enoyl-CoA_hydra_C
MCMDC2	Other/Unknown	no		P-loop_NTPase, MCM, MCM_lid
HENMT1	Other/Unknown	no		Hen1, SAM-dependent_MTases_sf
KASH5	Other/Unknown	no		EF-hand-dom_pair, KASH5_CC, KASH5
TERB1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, ARM-like
MEIOB	Other/Unknown	no		NA-bd_OB-fold, MEIOB, OB_MEIOB_N
MOV10L1	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
MSH5	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS_core, DNA_mismatch_repair_MutS_clamp
PDHA2	Other/Unknown	no		DH_E1, Pyrv_DH_E1_asu_subgrp-y, THDP-binding

Expression context

Cohort genes with no expression data: 0.

17 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)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	10
right testis	10
left testis	9
male germ line stem cell (sensu Vertebrata) in testis	7
buccal mucosa cell	3
oocyte	3
testis	3
adenohypophysis	2
pituitary gland	2
sperm	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
body of pancreas	1
esophagus mucosa	1
lower esophagus mucosa	1
ileal mucosa	1
ganglionic eminence	1
adult organism	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HID1	212	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DMC1	171	broad	marker	buccal mucosa cell, primordial germ cell in gonad, right testis
DMRT1	23	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
NPAS2	266	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, body of pancreas
TDRKH	194	ubiquitous	marker	primordial germ cell in gonad, right testis, left testis
GCNA	183	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, ileal mucosa
MCM8	226	ubiquitous	marker	primordial germ cell in gonad, buccal mucosa cell, oocyte
REC8	134	broad	marker	adenohypophysis, pituitary gland, ganglionic eminence
DDX25	191	broad	marker	left testis, right testis, adult organism
C14orf39	129	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
TDRD9	188	broad	yes	right testis, left testis, testis
HFM1	157	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, pituitary gland
FANCM	203	ubiquitous	marker	sperm, oocyte, male germ line stem cell (sensu Vertebrata) in testis
CDY2B	3		yes	colonic epithelium, ventricular zone, cortical plate
MCMDC2	157	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
HENMT1	214	ubiquitous	marker	oocyte, secondary oocyte, primordial germ cell in gonad
KASH5	112	tissue_specific	marker	right testis, left testis, testis
TERB1	141	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
MEIOB	154	broad	marker	right testis, left testis, primordial germ cell in gonad
MOV10L1	153	broad	marker	right testis, left testis, testis
MSH5	134	ubiquitous	yes	right uterine tube, right testis, left testis
PDHA2	23	tissue_specific	yes	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 20.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCM	2,764
DMC1	2,601
PDHA2	2,451
REC8	2,444
MEIOB	2,070
TDRD9	2,015
MCM8	1,952
HFM1	1,768
MSH5	1,572
KASH5	1,547

Intra-cohort edges

A	B	Sources
C14orf39	MCMDC2	string_interaction
C14orf39	MEIOB	string_interaction
C14orf39	TERB1	string_interaction
DMC1	KASH5	string_interaction
DMC1	MEIOB	string_interaction
DMC1	REC8	string_interaction
FANCM	MCM8	intact
HENMT1	MOV10L1	string_interaction
HENMT1	TDRD9	string_interaction
HENMT1	TDRKH	string_interaction
HFM1	MCM8	string_interaction
HFM1	MEIOB	string_interaction
HFM1	MSH5	string_interaction
HFM1	REC8	string_interaction
KASH5	TERB1	string_interaction
MCM8	MCMDC2	string_interaction
MCMDC2	REC8	string_interaction
MEIOB	TERB1	string_interaction
MOV10L1	TDRD9	string_interaction
MOV10L1	TDRKH	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 12 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DMC1	Q14565	10
MCM8	Q9UJA3	7
FANCM	Q8IYD8	7
TDRKH	Q9Y2W6	5
TERB1	Q8NA31	3
HENMT1	Q5T8I9	2
KASH5	Q8N6L0	2
DMRT1	Q9Y5R6	1
DDX25	Q9UHL0	1
CDY2B	Q9Y6F7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDHA2	P29803	94.08
HID1	Q8IV36	86.13
MCMDC2	Q4G0Z9	86.00
MSH5	O43196	82.36
MEIOB	Q8N635	81.00
TDRD9	Q8NDG6	80.45
MOV10L1	Q9BXT6	74.79
HFM1	A2PYH4	65.49
REC8	O95072	65.16
NPAS2	Q99743	61.78
GCNA	Q96QF7	59.13
C14orf39	Q8N1H7	58.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 22 evidence-associated genes (12 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 12 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	4	131.3×	6e-07	TDRKH, TDRD9, HENMT1, MOV10L1
Gene Silencing by RNA	3	89.2×	8e-05	TDRKH, TDRD9, MOV10L1
Meiotic recombination	2	21.6×	0.048	DMC1, MSH5
E2F mediated regulation of DNA replication	1	135.9×	0.051	MCM8
PDH complex synthesizes acetyl-CoA from PYR	1	135.9×	0.051	PDHA2
CDC6 association with the ORC:origin complex	1	119.0×	0.051	MCM8
E2F-enabled inhibition of pre-replication complex formation	1	105.7×	0.051	MCM8
DNA strand elongation	1	95.2×	0.051	MCM8
Unwinding of DNA	1	73.2×	0.054	MCM8
Regulation of pyruvate dehydrogenase (PDH) complex	1	59.5×	0.054	PDHA2
Transcriptional regulation of testis differentiation	1	59.5×	0.054	DMRT1
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	59.5×	0.054	NPAS2
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	39.6×	0.066	NPAS2
BMAL1:CLOCK,NPAS2 activates circadian expression	1	35.2×	0.066	NPAS2
Signaling by Retinoic Acid	1	34.0×	0.066	PDHA2
Activation of the pre-replicative complex	1	27.2×	0.066	MCM8
DNA Replication Pre-Initiation	1	26.4×	0.066	MCM8
Activation of ATR in response to replication stress	1	25.0×	0.066	MCM8
Switching of origins to a post-replicative state	1	25.0×	0.066	MCM8
Synthesis of DNA	1	25.0×	0.066	MCM8
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	24.4×	0.066	NPAS2
Meiosis	1	23.8×	0.066	MSH5
Fanconi Anemia Pathway	1	23.2×	0.066	FANCM
Cell Cycle	2	6.0×	0.066	MCM8, MSH5
Gene expression (Transcription)	3	4.5×	0.066	TDRKH, TDRD9, MOV10L1
DNA Replication	1	19.8×	0.073	MCM8
G1/S Transition	1	19.4×	0.073	MCM8
Heme signaling	1	18.0×	0.076	NPAS2
Reproduction	1	15.9×	0.080	MSH5
Mitotic G1 phase and G1/S transition	1	15.3×	0.080	MCM8

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
homologous chromosome pairing at meiosis	5	136.8×	8e-09	DMC1, C14orf39, KASH5, TERB1, MEIOB
male meiosis I	5	132.1×	8e-09	DMC1, REC8, TDRD9, MEIOB, MOV10L1
spermatogenesis	10	16.0×	8e-09	DMC1, TDRKH, REC8, C14orf39, TDRD9, CDY2B, MCMDC2, KASH5 (+2 more)
piRNA processing	4	153.2×	2e-07	TDRKH, TDRD9, HENMT1, MOV10L1
double-strand break repair involved in meiotic recombination	3	176.8×	1e-05	DMC1, MCMDC2, TERB1
fertilization	4	56.7×	1e-05	TDRKH, REC8, TDRD9, MEIOB
resolution of meiotic recombination intermediates	3	127.7×	2e-05	HFM1, FANCM, MEIOB
synaptonemal complex assembly	3	88.4×	6e-05	REC8, C14orf39, MCMDC2
male meiotic nuclear division	3	74.1×	9e-05	TDRKH, TDRD9, MEIOB
double-strand break repair via homologous recombination	4	28.4×	1e-04	MCM8, REC8, KASH5, MEIOB
oogenesis	3	52.2×	2e-04	C14orf39, MCMDC2, KASH5
meiotic telomere clustering	2	170.2×	5e-04	KASH5, TERB1
transposable element silencing by piRNA-mediated DNA methylation	2	102.1×	0.001	TDRD9, MOV10L1
female gamete generation	2	73.0×	0.002	DMC1, MCM8
spermatid development	3	19.8×	0.003	DMC1, REC8, DDX25
oocyte maturation	2	54.7×	0.004	DMC1, REC8
reciprocal meiotic recombination	2	51.1×	0.004	DMC1, REC8
telomere localization	1	766.0×	0.006	KASH5
late meiotic recombination nodule assembly	1	766.0×	0.006	MCMDC2
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1	766.0×	0.006	KASH5
recombinational interstrand cross-link repair	1	383.0×	0.010	MCM8
positive regulation of meiosis I	1	383.0×	0.010	DMRT1
secretory granule maturation	1	383.0×	0.010	HID1
mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication	1	383.0×	0.010	MCM8
regulation of nodal signaling pathway	1	383.0×	0.010	DMRT1
DNA recombinase assembly	1	255.3×	0.012	DMC1
male germ cell proliferation	1	255.3×	0.012	DMRT1
meiotic DNA double-strand break processing involved in reciprocal meiotic recombination	1	255.3×	0.012	C14orf39
vacuole fusion, non-autophagic	1	255.3×	0.012	HID1
meiotic cell cycle	2	22.2×	0.012	DMC1, REC8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 22

Druggability breadth: 2 of 22 evidence-associated genes (9%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HID1	0	0
DMC1	0	0
DMRT1	0	0
NPAS2	0	0
TDRKH	0	0
GCNA	0	0
MCM8	0	0
REC8	0	0
DDX25	0	0
C14orf39	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TERB1	1	Binding:1
PDHA2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDX25	3.6.4.13	RNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DDX25
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	21	HID1, DMC1, DMRT1, NPAS2, TDRKH, GCNA, MCM8, REC8, C14orf39, TDRD9 (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HID1	0	—
DMC1	0	—
DMRT1	0	—
NPAS2	0	—
TDRKH	0	—
GCNA	0	—
MCM8	0	—
REC8	0	—
DDX25	0	—
C14orf39	0	—
TDRD9	0	—
HFM1	0	—
FANCM	0	—
CDY2B	0	—
MCMDC2	0	—
HENMT1	0	—
KASH5	0	—
TERB1	1	—
MEIOB	0	—
MOV10L1	0	—
MSH5	0	—
PDHA2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 27.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	22
PHASE2	2
PHASE4	1
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT02275169	PHASE3	UNKNOWN	FSH Treatment for Non-obstructive Azoospermic Patients
NCT02041910	PHASE1/PHASE2	UNKNOWN	Testicular Injection of Autologous Stem Cells for Treatment of Patients With Azoospermia
NCT02544191	PHASE2	UNKNOWN	GnRHa Combined With hCG and hMG for Treatment of Patients With Non-obstructive Azoospermia
NCT03762967	PHASE2	UNKNOWN	Autologous Adipose-Derived Adult Stromal Vascular Cell Administration for Male Patients With Infertility
NCT02418832	Not specified	RECRUITING	Testis Needle Aspiration of Sperm in Men With Azoospermia
NCT05479474	Not specified	RECRUITING	Platelet Rich Plasma Testis Treatment for Infertile Men
NCT05628987	Not specified	RECRUITING	The Association of Gut Microbiota and Spermatogenic Dysfunction
NCT06841328	Not specified	RECRUITING	Fertility Enhancement Through Regenerative Treatment in Ovaries and Testes
NCT06941922	Not specified	RECRUITING	Testicular Evaluation of Azoospermia Using Micro-Ultrasound
NCT07074015	Not specified	RECRUITING	IntelliWell: An AI-Assisted Imaging Platform for Detection and Location of Ultra-Rare Testicular Sperm in Surgical Specimens
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)
NCT07542626	Not specified	RECRUITING	Fertility Restoration With Autografting of Cryopreserved Immature Testicular Tissue
NCT00282477	Not specified	UNKNOWN	Trial to Evaluate Erectile Function, Fertility and Sperm Count in Male Cyclists Compared to Age Matched Controls
NCT00484081	Not specified	COMPLETED	Microdissection Testicular Sperm Extraction (MicroTESE) and IVF-ICSI Outcome in Non-Obstructive Azoospermia (NOA)
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01375062	Not specified	COMPLETED	Obtaining Undifferentiated Cells From Testis Biopsy
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT02008799	Not specified	UNKNOWN	Intra Testicular Artery Injection of Bone Marrow Stem Cell in Management of Azoospermia
NCT02339272	Not specified	COMPLETED	Study of Synapsis and Recombination in Male Meiosis and the Implications in Infertility
NCT02414295	Not specified	COMPLETED	Sperm Production in Kleinfelter Syndrome Patients After Mesenchymal Stem Cell Injection
NCT02617173	Not specified	UNKNOWN	The Effect of Low Electrical Current on Testicular Spermatocyte Count
NCT02773498	Not specified	TERMINATED	Comparison of Medical Results of Testicular Sperm Extraction by Conventional Surgery and Microsurgical Track
NCT03497728	Not specified	TERMINATED	Detection of Microdeletions in the Azoospermia Factor (AZF) Regions in Infertile Male Patients
NCT04675164	Not specified	COMPLETED	Laser Assisted Sperm Selection of Viable Immotile Testicular Sperm in Azoospermic Infertile Men
NCT05866484	Not specified	COMPLETED	Testicular Sperm Aspiration (TESA) vs. Microfluidic Sperm Separation (MSS)
NCT06524258	Not specified	COMPLETED	Testicular Elastography for Microscopic Testicular Sperm Extraction

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MENOTROPINS	4	1
UROFOLLITROPIN	4	1
CHEMBL3249216	0	1
CHEMBL1233255	0	1