Spermatogenic failure 1

Summary

Spermatogenic failure 1 (MONDO:0009776) is a disease caused by SYCP2 (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: SYCP2 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 158

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 1
Mondo ID	MONDO:0009776
MeSH	C562902
OMIM	258150
DOID	DOID:0070188
SNOMED CT	236803007
UMLS	C0403810
MedGen	140793
GARD	0015214
Is cancer (heuristic)	no

Also known as: spermatogenic failure 1 · SPGF1

Data availability: 158 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › spermatogenic failure › spermatogenic failure 1

Related subtypes (112): spermatogenic failure 6, spermatogenic failure 2, spermatogenic failure 5, spermatogenic failure 4, spermatogenic failure, X-linked, 2, spermatogenic failure, Y-linked, 1, spermatogenic failure, Y-linked, 2, spermatogenic failure 3, spermatogenic failure 7, spermatogenic failure 8, spermatogenic failure 9, spermatogenic failure 10, spermatogenic failure 11, spermatogenic failure 12, spermatogenic failure 13, spermatogenic failure 14, spermatogenic failure 15, spermatogenic failure 16, spermatogenic failure 17, spermatogenic failure 30, spermatogenic failure 31, spermatogenic failure 32, spermatogenic failure 54, spermatogenic failure, X-linked, 4, spermatogenic failure, X-linked, 3, spermatogenic failure 33, spermatogenic failure 34, spermatogenic failure 55, spermatogenic failure 56, spermatogenic failure 57, spermatogenic failure 58, spermatogenic failure 59, spermatogenic failure 60, spermatogenic failure 61, spermatogenic failure 62, spermatogenic failure 63, spermatogenic failure 64, spermatogenic failure 65, spermatogenic failure 66, spermatogenic failure 67, spermatogenic failure 68, spermatogenic failure 69, spermatogenic failure 70, spermatogenic failure 71, spermatogenic failure 72, spermatogenic failure 73, spermatogenic failure 47, spermatogenic failure 48, spermatogenic failure 49, spermatogenic failure 50, spermatogenic failure 51, spermatogenic failure 52, spermatogenic failure 74, spermatogenic failure 75, spermatogenic failure 53, spermatogenic failure 76, spermatogenic failure 77, spermatogenic failure 35, spermatogenic failure 36, spermatogenic failure 37, spermatogenic failure 38, spermatogenic failure 39, spermatogenic failure 40, spermatogenic failure 41, spermatogenic failure 42, spermatogenic failure 43, spermatogenic failure 44, spermatogenic failure 45, spermatogenic failure 46, spermatogenic failure 18, spermatogenic failure 19, spermatogenic failure 20, spermatogenic failure 21, spermatogenic failure 22, spermatogenic failure 23, spermatogenic failure 24, spermatogenic failure 25, spermatogenic failure 26, spermatogenic failure 27, spermatogenic failure 28, spermatogenic failure 29, X-linked spermatogenic failure 1, spermatogenic failure 98, spermatogenic failure 78, spermatogenic failure 79, spermatogenic failure 80, spermatogenic failure, X-linked, 5, spermatogenic failure, X-linked, 6, spermatogenic failure 81, spermatogenic failure, X-linked, 7, spermatogenic failure 82, spermatogenic failure 83, spermatogenic failure 84, spermatogenic failure 85, spermatogenic failure 86, spermatogenic failure 87, spermatogenic failure 88, spermatogenic failure 89, spermatogenic failure 90, spermatogenic failure, X-linked, 8, spermatogenic failure 91, spermatogenic failure 92, spermatogenic failure 93, spermatogenic failure 94, spermatogenic failure 95, spermatogenic failure 96, spermatogenic failure 97, spermatogenic failure, X-linked, 9, spermatogenic failure 99, spermatogenic failure 100, spermatogenic failure 101, spermatogenic failure 102

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

158 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 32 pathogenic, 24 likely benign, 18 benign, 12 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 12 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068954	NM_004959.5(NR5A1):c.232_244del (p.Met78fs)	NR5A1	Pathogenic	criteria provided, single submitter
1075535	NM_004959.5(NR5A1):c.75C>G (p.Tyr25Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1075935	NM_004959.5(NR5A1):c.572del (p.Arg191fs)	NR5A1	Pathogenic	criteria provided, single submitter
1256011	NM_004959.5(NR5A1):c.250C>T (p.Arg84Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354651	NM_004959.5(NR5A1):c.231del (p.Met78fs)	NR5A1	Pathogenic	criteria provided, single submitter
1412226	NM_004959.5(NR5A1):c.895C>T (p.Gln299Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1442980	NM_004959.5(NR5A1):c.86C>T (p.Thr29Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454827	NM_004959.5(NR5A1):c.984del (p.Gln329fs)	NR5A1	Pathogenic	criteria provided, single submitter
1687572	NM_004959.5(NR5A1):c.259C>T (p.Arg87Cys)	NR5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2000749	NM_004959.5(NR5A1):c.1221C>A (p.Cys407Ter)	NR5A1	Pathogenic	criteria provided, single submitter
2019693	NM_004959.5(NR5A1):c.591C>G (p.Tyr197Ter)	NR5A1	Pathogenic	criteria provided, single submitter
2087543	NM_004959.5(NR5A1):c.1065_1138+158del	NR5A1	Pathogenic	criteria provided, single submitter
2092105	NM_004959.5(NR5A1):c.1106_1109del (p.Val369fs)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136807	NM_004959.5(NR5A1):c.205C>G (p.Arg69Gly)	NR5A1	Pathogenic	criteria provided, single submitter
2921914	NM_004959.5(NR5A1):c.601del (p.Tyr201fs)	NR5A1	Pathogenic	criteria provided, single submitter
2938097	NM_004959.5(NR5A1):c.64G>A (p.Gly22Ser)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2941241	NM_004959.5(NR5A1):c.236G>C (p.Arg79Pro)	NR5A1	Pathogenic	criteria provided, single submitter
2944523	NM_004959.5(NR5A1):c.245-2A>G	NR5A1	Pathogenic	criteria provided, single submitter
2947882	NM_004959.5(NR5A1):c.991-18C>A	NR5A1	Pathogenic	criteria provided, single submitter
3245234	NC_000009.11:g.(?127245037)(127267690_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3245235	NC_000009.11:g.(?127262349)(127267690_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3245237	NC_000009.11:g.(?127262449)(127265674_?)del	NR5A1	Pathogenic	criteria provided, single submitter
3596432	NM_004959.5(NR5A1):c.247G>A (p.Val83Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372437	NM_004959.5(NR5A1):c.937C>T (p.Arg313Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3755587	NM_004959.5(NR5A1):c.785_791del (p.Phe262fs)	NR5A1	Pathogenic	criteria provided, single submitter
3757286	NM_004959.5(NR5A1):c.105del (p.Phe36fs)	NR5A1	Pathogenic	criteria provided, single submitter
3757330	NM_004959.5(NR5A1):c.795del (p.Cys266fs)	NR5A1	Pathogenic	criteria provided, single submitter
3759840	NM_004959.5(NR5A1):c.1223_1224dup (p.Tyr409fs)	NR5A1	Pathogenic	criteria provided, single submitter
449434	NM_004959.5(NR5A1):c.938G>A (p.Arg313His)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783699	NM_004959.5(NR5A1):c.319C>T (p.Gln107Ter)	NR5A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
SYCP2	Strong	Autosomal dominant	spermatogenic failure 1

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TEX15	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
ANK2	Orphanet:101016	Romano-Ward syndrome
NR5A1	Orphanet:2138	46,XX ovotesticular difference of sex development
NR5A1	Orphanet:242	46,XY complete gonadal dysgenesis
NR5A1	Orphanet:243	46,XX gonadal dysgenesis
NR5A1	Orphanet:251510	46,XY partial gonadal dysgenesis
NR5A1	Orphanet:393	46,XX testicular difference of sex development
NR5A1	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

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYCP2	HGNC:11490	ENSG00000196074	Q9BX26	Synaptonemal complex protein 2	gencc,clinvar
TEX15	HGNC:11738	ENSG00000133863	Q9BXT5	Testis-expressed protein 15	clinvar
ANKRD36	HGNC:24079	ENSG00000135976	A6QL64	Ankyrin repeat domain-containing protein 36A	clinvar
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	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)
SYCP2	Synaptonemal complex protein 2	Major component of the axial/lateral elements of synaptonemal complexes (SCS) during meiotic prophase.
TEX15	Testis-expressed protein 15	Required during spermatogenesis for normal chromosome synapsis and meiotic recombination in germ cells.
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.
ANK2	Ankyrin-2	Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells.
NR5A1	Steroidogenic factor 1	Transcriptional activator.
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: 2 · Unknown: 4 · 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
Nuclear receptor	1	55.1×	0.054
Scaffold/PPI	2	4.9×	0.087
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYCP2	Other/Unknown	no		SYCP2-like, SYCP2_SLD, SYCP2_ARLD
TEX15	Other/Unknown	no		TEX15, TEX15_dom
ANKRD36	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, CC144C-like_CC_dom
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
NR5A1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PDHA2	Other/Unknown	no		DH_E1, Pyrv_DH_E1_asu_subgrp-y, THDP-binding

Expression context

Cohort genes with no expression data: 0.

5 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
male germ cell	2
sperm	2
oocyte	1
right testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
calcaneal tendon	1
corpus callosum	1
sural nerve	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
lateral nuclear group of thalamus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYCP2	192	broad	marker	right testis, oocyte, left testis
TEX15	76	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, male germ cell
ANKRD36	137	ubiquitous	marker	corpus callosum, calcaneal tendon, sural nerve
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
NR5A1	77	tissue_specific	yes	right adrenal gland cortex, right adrenal gland, left adrenal gland
PDHA2	23	tissue_specific	yes	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
PDHA2	2,451
NR5A1	2,146
DNAH1	1,699
TEX15	1,452
ANKRD36	1,330
SYCP2	803

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANK2	Q01484	11
NR5A1	Q13285	6
DNAH1	Q9P2D7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDHA2	P29803	94.08
SYCP2	Q9BX26	54.36
ANKRD36	A6QL64	50.82
TEX15	Q9BXT5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Meiosis	2	114.2×	0.004	SYCP2, TEX15
Reproduction	2	76.1×	0.004	SYCP2, TEX15
PDH complex synthesizes acetyl-CoA from PYR	1	326.3×	0.031	PDHA2
Regulation of pyruvate dehydrogenase (PDH) complex	1	142.8×	0.036	PDHA2
Transcriptional regulation of testis differentiation	1	142.8×	0.036	NR5A1
Cell Cycle	2	14.4×	0.036	SYCP2, TEX15
Transcriptional regulation of pluripotent stem cells	1	108.8×	0.039	NR5A1
Signaling by Retinoic Acid	1	81.6×	0.044	PDHA2
Interaction between L1 and Ankyrins	1	73.7×	0.044	ANK2
SUMOylation of intracellular receptors	1	67.2×	0.044	NR5A1
Nuclear Receptor transcription pathway	1	40.1×	0.062	NR5A1
Post-translational protein modification	2	7.7×	0.062	ANK2, NR5A1
SUMO E3 ligases SUMOylate target proteins	1	35.7×	0.064	NR5A1
SUMOylation	1	32.6×	0.065	NR5A1
Meiotic synapsis	1	28.2×	0.066	SYCP2
ER to Golgi Anterograde Transport	1	26.6×	0.066	ANK2
Meiotic recombination	1	25.9×	0.066	TEX15
L1CAM interactions	1	24.0×	0.066	ANK2
Developmental Biology	2	5.8×	0.066	ANK2, NR5A1
COPI-mediated anterograde transport	1	22.0×	0.067	ANK2
Transport to the Golgi and subsequent modification	1	20.6×	0.068	ANK2
Metabolism of proteins	2	5.0×	0.075	ANK2, NR5A1
Asparagine N-linked glycosylation	1	12.0×	0.105	ANK2
Axon guidance	1	9.0×	0.132	ANK2
Nervous system development	1	8.6×	0.133	ANK2
Membrane Trafficking	1	7.4×	0.147	ANK2
Vesicle-mediated transport	1	7.0×	0.151	ANK2
RNA Polymerase II Transcription	1	4.5×	0.218	NR5A1
Gene expression (Transcription)	1	3.6×	0.259	NR5A1
Generic Transcription Pathway	1	3.0×	0.290	NR5A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptonemal complex assembly	2	216.1×	0.002	SYCP2, TEX15
male meiotic nuclear division	2	181.2×	0.002	SYCP2, TEX15
protein localization to T-tubule	1	2808.7×	0.006	ANK2
atrial cardiac muscle cell to AV node cell communication	1	2808.7×	0.006	ANK2
SA node cell to atrial cardiac muscle cell communication	1	2808.7×	0.006	ANK2
primary sex determination	1	1404.3×	0.008	NR5A1
protein localization to M-band	1	1404.3×	0.008	ANK2
response to gonadotropin-releasing hormone	1	936.2×	0.010	NR5A1
regulation of atrial cardiac muscle cell action potential	1	936.2×	0.010	ANK2
negative regulation of female gonad development	1	702.2×	0.010	NR5A1
male genitalia morphogenesis	1	561.7×	0.010	SYCP2
sarcoplasmic reticulum calcium ion transport	1	561.7×	0.010	ANK2
membrane depolarization during SA node cell action potential	1	561.7×	0.010	ANK2
positive regulation of potassium ion import across plasma membrane	1	561.7×	0.010	ANK2
paranodal junction assembly	1	468.1×	0.010	ANK2
T-tubule organization	1	468.1×	0.010	ANK2
SA node cell action potential	1	468.1×	0.010	ANK2
regulation of SA node cell action potential	1	468.1×	0.010	ANK2
response to methylmercury	1	401.2×	0.010	ANK2
atrial septum development	1	351.1×	0.010	ANK2
pyruvate decarboxylation to acetyl-CoA	1	351.1×	0.010	PDHA2
protein localization to endoplasmic reticulum	1	351.1×	0.010	ANK2
luteinization	1	312.1×	0.010	NR5A1
tissue development	1	312.1×	0.010	NR5A1
negative regulation of developmental process	1	312.1×	0.010	SYCP2
female meiotic nuclear division	1	280.9×	0.010	SYCP2
sex determination	1	280.9×	0.010	NR5A1
atrial cardiac muscle cell action potential	1	280.9×	0.010	ANK2
positive regulation of male gonad development	1	280.9×	0.010	NR5A1
negative regulation of reproductive process	1	280.9×	0.010	SYCP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYCP2	0	0
TEX15	0	0
ANKRD36	0	0
DNAH1	0	0
ANK2	0	0
NR5A1	0	0
PDHA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR5A1	88	Binding:84, Functional:4
PDHA2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	NR5A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	SYCP2, TEX15, ANKRD36, DNAH1, ANK2, PDHA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYCP2	0	—
TEX15	0	—
ANKRD36	0	—
DNAH1	0	—
ANK2	0	—
NR5A1	88	—
PDHA2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.