Spermatogenic failure 4

Summary

Spermatogenic failure 4 (MONDO:0010052) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 4
Mondo ID	MONDO:0010052
MeSH	C536875
OMIM	270960
DOID	DOID:0070176
UMLS	C0232981
MedGen	68568
GARD	0015235
Is cancer (heuristic)	no

Also known as: arrest of spermatogenesis · azoospermia caused by mutation in SYCP3 · spermatogenic failure 4 · spermatogenic failure type 4 · SPGF4 · SYCP3 azoospermia

Data availability: 26 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 4

Related subtypes (112): spermatogenic failure 6, spermatogenic failure 2, spermatogenic failure 5, spermatogenic failure 1, 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

26 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 8 benign, 7 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332897	NM_001017975.6(HFM1):c.[2562_2563del;4126del]		Pathogenic	no assertion criteria provided
1332898	NM_001017975.6(HFM1):c.[2487_2491del;3490C>T]		Pathogenic	no assertion criteria provided
1332895	NM_001017975.6(HFM1):c.1355G>A (p.Arg452Gln)	HFM1	Pathogenic	no assertion criteria provided
1332896	NM_001017975.6(HFM1):c.1472T>C (p.Leu491Pro)	HFM1	Pathogenic	no assertion criteria provided
5371	NM_001177949.2(SYCP3):c.643del (p.Ile215fs)	SYCP3	Pathogenic	no assertion criteria provided
5372	NM_001177949.2(SYCP3):c.553-21_553-18del	SYCP3	Pathogenic	no assertion criteria provided
5373	NM_001177949.2(SYCP3):c.657T>C (p.Thr219=)	SYCP3	Pathogenic	no assertion criteria provided
883344	NM_001177949.2(SYCP3):c.*243C>G	CHPT1	Uncertain significance	criteria provided, single submitter
2474557	NM_001177949.2(SYCP3):c.291G>C (p.Lys97Asn)	SYCP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690174	NM_001177949.2(SYCP3):c.484C>T (p.Gln162Ter)	SYCP3	Uncertain significance	criteria provided, single submitter
306760	NM_001177949.2(SYCP3):c.*198G>A	SYCP3	Uncertain significance	criteria provided, single submitter
306765	NM_001177949.2(SYCP3):c.-64C>T	SYCP3	Uncertain significance	criteria provided, single submitter
3892583	NM_001177949.2(SYCP3):c.49G>C (p.Val17Leu)	SYCP3	Uncertain significance	criteria provided, single submitter
3892584	NM_001177949.2(SYCP3):c.502C>A (p.Gln168Lys)	SYCP3	Uncertain significance	criteria provided, single submitter
3892585	NM_001177949.2(SYCP3):c.514T>A (p.Leu172Met)	SYCP3	Uncertain significance	criteria provided, single submitter
880981	NM_001177949.2(SYCP3):c.28A>T (p.Arg10Trp)	SYCP3	Uncertain significance	criteria provided, single submitter
882343	NM_001177949.2(SYCP3):c.-74T>C	SYCP3	Uncertain significance	criteria provided, single submitter
306759	NM_001177949.2(SYCP3):c.*205G>A	CHPT1	Benign	criteria provided, multiple submitters, no conflicts
306762	NM_001177949.2(SYCP3):c.666A>G (p.Gln222=)	CHPT1	Benign	criteria provided, multiple submitters, no conflicts
306761	NM_001177949.2(SYCP3):c.*183A>G	SYCP3	Benign	criteria provided, single submitter
306764	NM_001177949.2(SYCP3):c.435A>G (p.Glu145=)	SYCP3	Benign	criteria provided, multiple submitters, no conflicts
306766	NM_001177949.2(SYCP3):c.-122T>A	SYCP3	Benign	criteria provided, multiple submitters, no conflicts
880979	NM_001177949.2(SYCP3):c.80T>C (p.Phe27Ser)	SYCP3	Likely benign	criteria provided, single submitter
880980	NM_001177949.2(SYCP3):c.59A>G (p.Gln20Arg)	SYCP3	Benign	criteria provided, single submitter
880982	NM_001177949.2(SYCP3):c.-53C>G	SYCP3	Benign	criteria provided, single submitter
882344	NM_001177949.2(SYCP3):c.-106A>G	SYCP3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
SYCP3	Limited	Autosomal dominant	spermatogenic failure 4	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYCP3	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYCP3	HGNC:18130	ENSG00000139351	Q8IZU3	Synaptonemal complex protein 3	gencc,clinvar
CHPT1	HGNC:17852	ENSG00000111666	Q8WUD6	Cholinephosphotransferase 1	clinvar
HFM1	HGNC:20193	ENSG00000162669	A2PYH4	Probable ATP-dependent DNA helicase HFM1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYCP3	Synaptonemal complex protein 3	Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase.
CHPT1	Cholinephosphotransferase 1	Catalyzes the final step of de novo phosphatidylcholine (PC) synthesis, i.e. the transfer of choline phosphate from CDP-choline to the free hydroxyl of a diacylglycerol (DAG), producing a PC.
HFM1	Probable ATP-dependent DNA helicase HFM1	Required for crossover formation and complete synapsis of homologous chromosomes during meiosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYCP3	Other/Unknown	no		XLR/SYCP3/FAM9_dom, XLR/SYCP3
CHPT1	Enzyme (other)	yes	2.7.8.2	CDP-OH_P_trans, CHOPT, CDP-OH_PTrfase_TM_dom
HFM1	Other/Unknown	no		Helicase_C-like, Sec63-dom, DEAD/DEAH_box_helicase_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
secondary oocyte	1
heart right ventricle	1
jejunal mucosa	1
parotid gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYCP3	170	tissue_specific	marker	right testis, left testis, secondary oocyte
CHPT1	290	ubiquitous	marker	jejunal mucosa, parotid gland, heart right ventricle
HFM1	157	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HFM1	1,768
SYCP3	1,619
CHPT1	1,352

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SYCP3	Q8IZU3	1
CHPT1	Q8WUD6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HFM1	A2PYH4	65.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PC	1	203.9×	0.017	CHPT1
Meiosis	1	142.8×	0.017	SYCP3
Reproduction	1	95.2×	0.017	SYCP3
Meiotic synapsis	1	70.5×	0.018	SYCP3
Cell Cycle	1	18.0×	0.055	SYCP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
platelet activating factor biosynthetic process	1	1404.3×	0.005	CHPT1
CDP-choline pathway	1	1123.5×	0.005	CHPT1
resolution of meiotic recombination intermediates	1	312.1×	0.008	HFM1
sperm DNA condensation	1	295.6×	0.008	SYCP3
phosphatidylcholine biosynthetic process	1	267.5×	0.008	CHPT1
male meiosis I	1	193.7×	0.009	SYCP3
meiotic cell cycle	1	81.4×	0.019	SYCP3
regulation of cell growth	1	73.9×	0.019	CHPT1
spermatid development	1	48.4×	0.025	SYCP3
lipid metabolic process	1	30.5×	0.036	CHPT1
cell division	1	15.4×	0.064	SYCP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYCP3	0	0
CHPT1	0	0
HFM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHPT1	2.7.8.2	diacylglycerol cholinephosphotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	CHPT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SYCP3, HFM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYCP3	0	—
CHPT1	0	—
HFM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.