Oligospermia

Summary

Oligospermia (MONDO:0001913) is a disease with 21 cohort genes and 26 clinical trials. Top therapeutic interventions include lisinopril anhydrous, anastrozole, and isotretinoin.

At a glance

• Cohort genes: 21
• ClinVar variants: 23
• Clinical trials: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	oligospermia
Mondo ID	MONDO:0001913
MeSH	D009845
DOID	DOID:14228
ICD-10-CM	N46.1
ICD-11	1497721709
UMLS	C0028960
MedGen	18162
Is cancer (heuristic)	no

Data availability: 23 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

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

Related subtypes (7): infertility due to extratesticular cause, 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

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:

10 uncertain significance, 6 likely pathogenic, 4 pathogenic, 1 conflicting classifications of pathogenicity, 1 association, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3239654	NM_001372106.1(DNAH10):c.3904C>T (p.Arg1302Ter)	DNAH10	Pathogenic	criteria provided, single submitter
3239649	NM_173651.4(FSIP2):c.2689del (p.Ser897fs)	FSIP2	Pathogenic	criteria provided, single submitter
869115	NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)	MSH4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239638	NM_031293.3(PMFBP1):c.361C>T (p.Gln121Ter)	PMFBP1	Pathogenic	criteria provided, single submitter
3239652	NM_001366900.1(TTC21A):c.3450+2del	TTC21A	Pathogenic	criteria provided, single submitter
3239639	NM_006201.5(CDK16):c.43C>T (p.Leu15Phe)	CDK16	Likely pathogenic	criteria provided, single submitter
3239653	NM_025145.7(CFAP43):c.3101A>C (p.Lys1034Thr)	CFAP43	Likely pathogenic	criteria provided, single submitter
3239655	NM_015512.5(DNAH1):c.6692C>T (p.Thr2231Met)	DNAH1	Likely pathogenic	criteria provided, single submitter
1330303	NM_001271862.2(PNLDC1):c.743G>A (p.Gly248Asp)	PNLDC1	Likely pathogenic	criteria provided, single submitter
3239648	NM_032018.7(SPRTN):c.1246_1247del (p.Val416fs)	SPRTN	Likely pathogenic	criteria provided, single submitter
816940	NM_002536.4(TBC1D25):c.4609C>T	TBC1D25	Likely pathogenic	criteria provided, single submitter
374019	NM_000523.4(HOXD13):c.820C>T (p.Arg274Ter)	HOXD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267893	46;XY;t(20;22)(q13.3;q11.2)		Uncertain significance	criteria provided, single submitter
267936	46;XY;t(12;14)(q15;q13)mat		Uncertain significance	criteria provided, single submitter
3239640	NM_006201.5(CDK16):c.47G>A (p.Arg16Gln)	CDK16	Uncertain significance	criteria provided, single submitter
3239642	NM_001079872.2(CUL4B):c.648G>C (p.Lys216Asn)	CUL4B	Uncertain significance	criteria provided, single submitter
2391262	NM_138435.4(FAM83F):c.671G>A (p.Arg224His)	FAM83F	Uncertain significance	criteria provided, multiple submitters, no conflicts
3239651	NM_005316.4(GTF2H1):c.1393T>C (p.Tyr465His)	GTF2H1	Uncertain significance	criteria provided, single submitter
830043	NM_004798.4(KIF3B):c.1032A>T (p.Pro344=)	KIF3B	association	no assertion criteria provided
2445465	NM_005634.3(SOX3):c.64C>G (p.Arg22Gly)	LOC108281134	Uncertain significance	criteria provided, single submitter
3239650	NM_006341.4(MAD2L2):c.103G>A (p.Glu35Lys)	MAD2L2	Uncertain significance	criteria provided, single submitter
1001481	NM_015072.5(TTLL5):c.989T>A (p.Leu330Gln)	TTLL5	Uncertain significance	criteria provided, multiple submitters, no conflicts
3239641	NM_031907.3(USP26):c.125T>C (p.Phe42Ser)	USP26	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 22 · 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
RPL10L	Moderate	Autosomal dominant	oligospermia	3
TDRD6	Limited	Autosomal recessive	oligospermia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPL10L	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
USP26	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
PMFBP1	Orphanet:529970	Male infertility due to acephalic spermatozoa
TTLL5	Orphanet:1872	Cone rod dystrophy
PNLDC1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FSIP2	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
SPRTN	Orphanet:435953	Progeroid features-hepatocellular carcinoma predisposition syndrome
CUL4B	Orphanet:85293	X-linked intellectual disability, Cabezas type
CFAP43	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
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
TTC21A	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
HOXD13	Orphanet:295191	Zygodactyly type 3
HOXD13	Orphanet:295195	Synpolydactyly type 1
HOXD13	Orphanet:887	VACTERL/VATER association
HOXD13	Orphanet:93387	Brachydactyly type E
HOXD13	Orphanet:93406	Syndactyly type 5
HOXD13	Orphanet:93409	Brachydactyly-syndactyly, Zhao type
MAD2L2	Orphanet:84	Fanconi anemia
MSH4	Orphanet:243	46,XX gonadal dysgenesis

Cohort genes → proteins

21 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPL10L	HGNC:17976	ENSG00000165496	Q96L21	Ribosomal protein uL16-like	gencc
TDRD6	HGNC:21339	ENSG00000180113	O60522	Tudor domain-containing protein 6	gencc
USP26	HGNC:13485	ENSG00000134588	Q9BXU7	Ubiquitin carboxyl-terminal hydrolase 26	clinvar
PMFBP1	HGNC:17728	ENSG00000118557	Q8TBY8	Polyamine-modulated factor 1-binding protein 1	clinvar
TTLL5	HGNC:19963	ENSG00000119685	Q6EMB2	Tubulin polyglutamylase TTLL5	clinvar
PNLDC1	HGNC:21185	ENSG00000146453	Q8NA58	Poly(A)-specific ribonuclease PNLDC1	clinvar
FSIP2	HGNC:21675	ENSG00000188738	Q5CZC0	Fibrous sheath-interacting protein 2	clinvar
SACK1F	HGNC:25148	ENSG00000133477	Q8NEG4	Protein FAM83F	clinvar
SPRTN	HGNC:25356	ENSG00000010072	Q9H040	DNA-dependent metalloprotease SPRTN	clinvar
CUL4B	HGNC:2555	ENSG00000158290	Q13620	Cullin-4B	clinvar
CFAP43	HGNC:26684	ENSG00000197748	Q8NDM7	Cilia- and flagella-associated protein 43	clinvar
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	clinvar
DNAH10	HGNC:2941	ENSG00000197653	Q8IVF4	Dynein axonemal heavy chain 10	clinvar
TTC21A	HGNC:30761	ENSG00000168026	Q8NDW8	Tetratricopeptide repeat protein 21A	clinvar
GTF2H1	HGNC:4655	ENSG00000110768	P32780	General transcription factor IIH subunit 1	clinvar
HOXD13	HGNC:5136	ENSG00000128714	P35453	Homeobox protein Hox-D13	clinvar
KIF3B	HGNC:6320	ENSG00000101350	O15066	Kinesin-like protein KIF3B	clinvar
MAD2L2	HGNC:6764	ENSG00000116670	Q9UI95	Mitotic spindle assembly checkpoint protein MAD2B	clinvar
MSH4	HGNC:7327	ENSG00000057468	O15457	MutS protein homolog 4	clinvar
TBC1D25	HGNC:8092	ENSG00000068354	Q3MII6	TBC1 domain family member 25	clinvar
CDK16	HGNC:8749	ENSG00000102225	Q00536	Cyclin-dependent kinase 16	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPL10L	Ribosomal protein uL16-like	Testis-specific component of the ribosome, which is required for the transition from prophase to metaphase in male meiosis I.
TDRD6	Tudor domain-containing protein 6	Tudor domain-containing protein involved in germ cell development, more specifically the formation of chromatoid body (during spermiogenesis), Balbiani body (during oogenesis), germ plasm (upon fertilization), and for proper miRNA expressi…
USP26	Ubiquitin carboxyl-terminal hydrolase 26	Deubiquitinase regulating several biological processes through the deubiquitination of components of these processes.
PMFBP1	Polyamine-modulated factor 1-binding protein 1	Required for normal spermatogenesis.
TTLL5	Tubulin polyglutamylase TTLL5	Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin.
PNLDC1	Poly(A)-specific ribonuclease PNLDC1	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.
FSIP2	Fibrous sheath-interacting protein 2	Plays a role in spermatogenesis.
SPRTN	DNA-dependent metalloprotease SPRTN	DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity.
CUL4B	Cullin-4B	Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
CFAP43	Cilia- and flagella-associated protein 43	Flagellar protein involved in sperm flagellum axoneme organization and function.
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.
DNAH10	Dynein axonemal heavy chain 10	Force generating protein of respiratory cilia.
TTC21A	Tetratricopeptide repeat protein 21A	Intraflagellar transport (IFT)-associated protein required for spermatogenesis.
GTF2H1	General transcription factor IIH subunit 1	Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription…
HOXD13	Homeobox protein Hox-D13	Sequence-specific transcription factor that binds gene promoters and activates their transcription.
KIF3B	Kinesin-like protein KIF3B	Microtubule-based molecular motor that transport intracellular cargos, such as vesicles, organelles and protein complexes.
MAD2L2	Mitotic spindle assembly checkpoint protein MAD2B	Adapter protein able to interact with different proteins and involved in different biological processes.
MSH4	MutS protein homolog 4	Involved in meiotic recombination.
TBC1D25	TBC1 domain family member 25	Acts as a GTPase-activating protein specific for RAB33B.
CDK16	Cyclin-dependent kinase 16	Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 16 · Druggable fraction: 0.14

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	16	1.4×	0.273
Protease	1	1.7×	0.934
Kinase	1	1.3×	0.934
Scaffold/PPI	1	0.8×	0.934
Enzyme (other)	1	0.6×	0.934
Transcription factor	1	0.4×	0.934

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPL10L	Other/Unknown	no		Ribosomal_uL16_euk_arch, Ribosomal_uL16_dom, Ribosomal_uL16_CS_euk_arc
TDRD6	Other/Unknown	no		Tudor, SNase_OB-fold_sf, Tudor_TDRD6_rpt1
USP26	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
PMFBP1	Other/Unknown	no		PMF1-bd
TTLL5	Other/Unknown	no		TTL/TTLL_fam
PNLDC1	Enzyme (other)	yes	3.1.13.4	RNase_CAF1, RNaseH-like_sf, RNaseH_sf
FSIP2	Other/Unknown	no		FSIP2_C, FSIP2
SACK1F	Other/Unknown	no		SACK1, FAM83
SPRTN	Other/Unknown	no		SprT-like_domain, Rad18_UBZ4, Spartan
CUL4B	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
CFAP43	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4
DNAH10	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
TTC21A	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
GTF2H1	Other/Unknown	no		BSD_dom, PH-like_dom_sf, TFIIH_BTF_p62_N
HOXD13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
KIF3B	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
MAD2L2	Other/Unknown	no		HORMA_dom, HORMA_dom_sf, Mad2-like
MSH4	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS_core, DNA_mmatch_repair_MutS_con_dom
TBC1D25	Other/Unknown	no		Rab-GAP-TBC_dom, Rab-GAP_TBC_sf
CDK16	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	6
right testis	5
sperm	5
male germ line stem cell (sensu Vertebrata) in testis	4
primordial germ cell in gonad	4
right uterine tube	4
oocyte	3
secondary oocyte	2
male germ cell	2
ileal mucosa	2
bronchial epithelial cell	2
cortical plate	2
buccal mucosa cell	1
testis	1
corpus epididymis	1
mucosa of paranasal sinus	1
bronchus	1
olfactory segment of nasal mucosa	1
adrenal tissue	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPL10L	116	tissue_specific	yes	left testis, right testis, sperm
TDRD6	199	tissue_specific	marker	secondary oocyte, oocyte, sperm
USP26	62	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, buccal mucosa cell
PMFBP1	169	tissue_specific	marker	sperm, male germ cell, right testis
TTLL5	288	ubiquitous	marker	left testis, right testis, testis
PNLDC1	155	tissue_specific	yes	oocyte, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
FSIP2	159	tissue_specific	marker	sperm, male germ line stem cell (sensu Vertebrata) in testis, left testis
SACK1F	192	broad	marker	left testis, right testis, ileal mucosa
SPRTN	223	ubiquitous	yes	oocyte, secondary oocyte, primordial germ cell in gonad
CUL4B	291	ubiquitous	marker	sperm, male germ cell, corpus epididymis
CFAP43	190	broad	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
DNAH10	134	tissue_specific	marker	right uterine tube, cortical plate, olfactory segment of nasal mucosa
TTC21A	173	ubiquitous	marker	right uterine tube, left testis, right testis
GTF2H1	146	ubiquitous	marker	calcaneal tendon, adrenal tissue, corpus callosum
HOXD13	47	tissue_specific	marker	urethra, vagina, muscle layer of sigmoid colon
KIF3B	287	ubiquitous	marker	middle temporal gyrus, cortical plate, islet of Langerhans
MAD2L2	229	ubiquitous	marker	embryo, ganglionic eminence, left testis
MSH4	145	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right coronary artery
TBC1D25	188	ubiquitous	marker	ileal mucosa, tibialis anterior, granulocyte
CDK16	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL4B	4,342
CDK16	3,613
RPL10L	3,564
SPRTN	2,941
MAD2L2	2,283
GTF2H1	1,899
DNAH1	1,699
MSH4	1,647
KIF3B	1,488
DNAH10	1,481

Intra-cohort edges

A	B	Sources
CDK16	TBC1D25	intact
CFAP43	DNAH1	string_interaction
CFAP43	FSIP2	string_interaction
CFAP43	TTC21A	string_interaction
DNAH1	FSIP2	string_interaction
DNAH1	TTC21A	string_interaction
DNAH10	TTC21A	string_interaction
FSIP2	TTC21A	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 11 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL10L	Q96L21	114
GTF2H1	P32780	52
MAD2L2	Q9UI95	24
CUL4B	Q13620	5
SPRTN	Q9H040	3
CDK16	Q00536	3
DNAH1	Q9P2D7	2
TTLL5	Q6EMB2	1
CFAP43	Q8NDM7	1
KIF3B	O15066	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNLDC1	Q8NA58	90.16
TTC21A	Q8NDW8	81.32
PMFBP1	Q8TBY8	77.80
MSH4	O15457	75.12
TBC1D25	Q3MII6	71.10
SACK1F	Q8NEG4	68.18
TDRD6	O60522	64.82
USP26	Q9BXU7	60.28
HOXD13	P35453	57.18
FSIP2	Q5CZC0
DNAH10	Q8IVF4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 98. Enrichment computed across 21 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
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	2	415.3×	4e-04	SPRTN, MAD2L2
DNA Damage Bypass	2	415.3×	4e-04	SPRTN, MAD2L2
DNA Repair	3	26.9×	0.005	SPRTN, GTF2H1, MAD2L2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	48.3×	0.013	CUL4B, GTF2H1
Dual Incision in GG-NER	2	47.2×	0.013	CUL4B, GTF2H1
Formation of Incision Complex in GG-NER	2	46.1×	0.013	CUL4B, GTF2H1
Formation of TC-NER Pre-Incision Complex	2	38.5×	0.016	CUL4B, GTF2H1
Gap-filling DNA repair synthesis and ligation in TC-NER	2	32.4×	0.019	CUL4B, GTF2H1
Dual incision in TC-NER	2	31.5×	0.019	CUL4B, GTF2H1
Translesion synthesis by REV1	1	64.9×	0.103	MAD2L2
Translesion synthesis by POLI	1	61.1×	0.103	MAD2L2
Translesion synthesis by POLK	1	57.7×	0.103	MAD2L2
Translesion Synthesis by POLH	1	54.6×	0.103	SPRTN
Global Genome Nucleotide Excision Repair (GG-NER)	1	41.5×	0.103	GTF2H1
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	37.1×	0.103	GTF2H1
RNA Pol II CTD phosphorylation and interaction with CE	1	37.1×	0.103	GTF2H1
PIWI-interacting RNA (piRNA) biogenesis	1	35.8×	0.103	TDRD6
Recognition of DNA damage by PCNA-containing replication complex	1	34.6×	0.103	CUL4B
mRNA Capping	1	34.6×	0.103	GTF2H1
Rab regulation of trafficking	1	33.5×	0.103	TBC1D25
Gene Silencing by RNA	1	32.4×	0.103	TDRD6
Formation of the Early Elongation Complex	1	30.5×	0.103	GTF2H1
Formation of the HIV-1 Early Elongation Complex	1	30.5×	0.103	GTF2H1
HIV Transcription Elongation	1	30.5×	0.103	GTF2H1
RNA Polymerase I Transcription Termination	1	29.7×	0.103	GTF2H1
RNA Polymerase I Promoter Clearance	1	26.6×	0.103	GTF2H1
Meiosis	1	25.9×	0.103	MSH4
DNA Damage Recognition in GG-NER	1	25.9×	0.103	CUL4B
Nucleotide Excision Repair	1	25.9×	0.103	GTF2H1
RNA Polymerase I Transcription	1	25.9×	0.103	GTF2H1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sperm axoneme assembly	4	89.2×	1e-05	TTLL5, FSIP2, CFAP43, DNAH1
spermatogenesis	7	11.7×	7e-05	USP26, PMFBP1, RPL10L, PNLDC1, TDRD6, MSH4, CDK16
translesion synthesis	2	89.2×	0.009	SPRTN, MAD2L2
piRNA processing	2	80.2×	0.009	PNLDC1, TDRD6
flagellated sperm motility	3	16.7×	0.018	FSIP2, DNAH1, TTC21A
DNA damage response, signal transduction resulting in transcription	1	802.5×	0.020	MAD2L2
branch elongation of an epithelium	1	802.5×	0.020	HOXD13
protein localization to cilium	2	38.2×	0.020	FSIP2, TTC21A
opsin transport	1	401.2×	0.029	KIF3B
priRNA 3’-end processing	1	401.2×	0.029	PNLDC1
siRNA 3’-end processing	1	401.2×	0.029	PNLDC1
embryonic hindgut morphogenesis	1	267.5×	0.040	HOXD13
somatic diversification of immunoglobulins involved in immune response	1	200.6×	0.042	MAD2L2
morphogenesis of an epithelial fold	1	200.6×	0.042	HOXD13
G1/S transition of mitotic cell cycle	2	19.1×	0.042	USP26, CUL4B
regulation of branching involved in prostate gland morphogenesis	1	160.5×	0.043	HOXD13
negative regulation of ubiquitin protein ligase activity	1	160.5×	0.043	MAD2L2
mitotic centrosome separation	1	133.8×	0.043	KIF3B
growth hormone secretion	1	133.8×	0.043	CDK16
P granule organization	1	133.8×	0.043	TDRD6
plus-end-directed vesicle transport along microtubule	1	133.8×	0.043	KIF3B
regulation of autophagosome maturation	1	133.8×	0.043	TBC1D25
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	114.6×	0.046	HOXD13
anterograde dendritic transport of neurotransmitter receptor complex	1	114.6×	0.046	KIF3B
spermatid development	2	13.8×	0.046	PMFBP1, TTC21A
regulation of cilium beat frequency	1	100.3×	0.048	CFAP43
telomere maintenance in response to DNA damage	1	89.2×	0.051	MAD2L2
regulation of cell cycle phase transition	1	89.2×	0.051	CDK16
protein-DNA covalent cross-linking repair	1	80.2×	0.054	SPRTN
error-prone translesion synthesis	1	73.0×	0.054	MAD2L2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 20

Druggability breadth: 4 of 21 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
CDK16	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK16	50	4
RPL10L	0	0
TDRD6	0	0
USP26	0	0
PMFBP1	0	0
TTLL5	0	0
PNLDC1	0	0
FSIP2	0	0
SACK1F	0	0
SPRTN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	CDK16
PONATINIB	4	CDK16
RUCAPARIB	4	CDK16
FEDRATINIB	4	CDK16
AXITINIB	4	CDK16
NERATINIB	4	CDK16
PALBOCICLIB	4	CDK16
DABRAFENIB	4	CDK16
PACRITINIB	4	CDK16
BOSUTINIB	4	CDK16
ABEMACICLIB	4	CDK16
RIBOCICLIB	4	CDK16
PAZOPANIB	4	CDK16
NINTEDANIB	4	CDK16
SUNITINIB	4	CDK16
QUIZARTINIB	4	CDK16
DINACICLIB	3	CDK16
LINIFANIB	3	CDK16
ENZASTAURIN	3	CDK16
ALVOCIDIB	3	CDK16
DOVITINIB	3	CDK16
LESTAURTINIB	3	CDK16
RUBOXISTAURIN	3	CDK16
INDIRUBIN	2	CDK16
SILMITASERTIB	2	CDK16
FORETINIB	2	CDK16
TANDUTINIB	2	CDK16
SELICICLIB	2	CDK16
SU-014813	2	CDK16
REBASTINIB	2	CDK16

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CDK16	259	Binding:259
CUL4B	5	Binding:5
KIF3B	4	Binding:4
MAD2L2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNLDC1	3.1.13.4	poly(A)-specific ribonuclease
CDK16	2.7.11.22	cyclin-dependent kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CDK16	259

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

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

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)
MOMELOTINIB	4	CDK16
PONATINIB	4	CDK16
RUCAPARIB	4	CDK16
FEDRATINIB	4	CDK16
AXITINIB	4	CDK16
NERATINIB	4	CDK16
PALBOCICLIB	4	CDK16
DABRAFENIB	4	CDK16
PACRITINIB	4	CDK16
BOSUTINIB	4	CDK16
ABEMACICLIB	4	CDK16
RIBOCICLIB	4	CDK16
PAZOPANIB	4	CDK16
NINTEDANIB	4	CDK16
SUNITINIB	4	CDK16
QUIZARTINIB	4	CDK16
DINACICLIB	3	CDK16
LINIFANIB	3	CDK16
ENZASTAURIN	3	CDK16
ALVOCIDIB	3	CDK16
DOVITINIB	3	CDK16
LESTAURTINIB	3	CDK16
RUBOXISTAURIN	3	CDK16
INDIRUBIN	2	CDK16
SILMITASERTIB	2	CDK16
FORETINIB	2	CDK16
TANDUTINIB	2	CDK16
SELICICLIB	2	CDK16
SU-014813	2	CDK16
REBASTINIB	2	CDK16

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK16
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	USP26, PNLDC1
E	Difficult family or no structure, no drug	18	RPL10L, TDRD6, PMFBP1, TTLL5, FSIP2, SACK1F, SPRTN, CUL4B, CFAP43, DNAH1 (+8 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RPL10L	0	—
TDRD6	0	—
USP26	0	—
PMFBP1	0	—
TTLL5	0	—
PNLDC1	0	—
FSIP2	0	—
SACK1F	0	—
SPRTN	0	—
CUL4B	5	—
CFAP43	0	—
DNAH1	0	—
DNAH10	0	—
TTC21A	0	—
GTF2H1	0	—
HOXD13	0	—
KIF3B	4	—
MAD2L2	1	—
MSH4	0	—
TBC1D25	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 26.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE4	3
PHASE2	3
EARLY_PHASE1	2
PHASE3	1
PHASE2/PHASE3	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT02063256	PHASE2/PHASE3	UNKNOWN	7 NUTS Study. Diet Modification and Male Fertility.
NCT06869863	PHASE1/PHASE2	RECRUITING	Study of Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of the Medicinal Product MediReg®
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT05158114	PHASE1	WITHDRAWN	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Testicular Injury and Oligospermia
NCT00479960	EARLY_PHASE1	UNKNOWN	A Preliminary Study on Effect of Omega-3 on Human Sperm
NCT06342856	EARLY_PHASE1	UNKNOWN	Evaluation of Treatment With Coenzyme Q10 and L-Carnitine on Semen Parameters in Infertile Men With Idiopathic Oligoasthenoteratospermia
NCT05842239	Not specified	RECRUITING	Hyperbaric Oxygen Therapy for Men Suffering From Infertility Due to Oligospermia.
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01239186	Not specified	COMPLETED	Identification and Characterization of the Methylation Abnormalities on Whole Genome Among Infertile Men
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT01520584	Not specified	UNKNOWN	Supplement Intake in Infertile Men;the Effect on Sperm Parameters,Fertilization Rate and Embryo Quality
NCT01828710	Not specified	COMPLETED	Myo-inositol on Human Semen Parameters
NCT01856361	Not specified	TERMINATED	Ramipril for the Treatment of Oligospermia
NCT02155179	Not specified	COMPLETED	Sperm Pathology Samples and Morphokinetics
NCT03898752	Not specified	COMPLETED	Is Oxidative Stress in Semen Reduced by Lifestyle Intervention
NCT04349345	Not specified	COMPLETED	Seminal Fluid’s Changes Over 20 Years
NCT04795440	Not specified	COMPLETED	Comparison of ICSI Outcomes in Cycles Using Testicular and Ejaculate Sperm From Couples With High SDF
NCT05506722	Not specified	UNKNOWN	Using of Testes Shocker in Improving the Spermatogenesis and Sperms Activity
NCT06202469	Not specified	COMPLETED	Creatine and Ubiquinol for Sperm Quality

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LISINOPRIL ANHYDROUS	4	2
ANASTROZOLE	4	1
ISOTRETINOIN	4	1
INOSITOL	3	1
CHEMBL1950780	0	1