Spermatogenic failure 17

Summary

Spermatogenic failure 17 (MONDO:0014970) is a disease caused by PLCZ1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PLCZ1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 17
Mondo ID	MONDO:0014970
OMIM	617214
DOID	DOID:0070174
UMLS	C4310666
MedGen	934633
Is cancer (heuristic)	no

Also known as: azoospermia caused by mutation in PLCZ1 · PLCZ1 azoospermia · spermatogenic failure 17 · spermatogenic failure 17; SPGF17 · spermatogenic failure type 17 · SPGF17

Data availability: 15 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 17

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

15 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 uncertain significance, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2578004	NM_033123.4(PLCZ1):c.1174+3A>C	PIK3C2G	Pathogenic	no assertion criteria provided
2578005	NM_033123.4(PLCZ1):c.1274A>G (p.Asn425Ser)	PIK3C2G	Pathogenic	no assertion criteria provided
2578006	NM_033123.4(PLCZ1):c.136-1G>C	PIK3C2G	Pathogenic	no assertion criteria provided
2578007	NM_033123.4(PLCZ1):c.1358G>A (p.Gly453Asp)	PIK3C2G	Pathogenic	no assertion criteria provided
978089	NM_033123.4(PLCZ1):c.588C>A (p.Cys196Ter)	PIK3C2G	Pathogenic	no assertion criteria provided
978090	NM_033123.4(PLCZ1):c.1048T>C (p.Ser350Pro)	PIK3C2G	Pathogenic	no assertion criteria provided
978091	NM_033123.4(PLCZ1):c.736C>T (p.Leu246Phe)	PIK3C2G	Pathogenic	no assertion criteria provided
1324931	NM_033123.4(PLCZ1):c.193C>T (p.Arg65Ter)	PIK3C2G	Likely pathogenic	criteria provided, single submitter
271283	NM_033123.4(PLCZ1):c.1465A>T (p.Ile489Phe)	PIK3C2G	Likely pathogenic	criteria provided, single submitter
4531235	NM_033123.4(PLCZ1):c.949+1G>A	PIK3C2G	Likely pathogenic	criteria provided, single submitter
4796511	NM_033123.4(PLCZ1):c.590G>A (p.Arg197His)	PIK3C2G	Likely pathogenic	criteria provided, single submitter
1031034	NM_033123.4(PLCZ1):c.1154G>A (p.Arg385Gln)	PIK3C2G	Uncertain significance	criteria provided, single submitter
3769635	NM_033123.4(PLCZ1):c.1251T>A (p.Asn417Lys)	PIK3C2G	Uncertain significance	no assertion criteria provided
3892105	NM_033123.4(PLCZ1):c.1171C>T (p.Arg391Ter)	PIK3C2G	Uncertain significance	criteria provided, single submitter
4533250	NM_033123.4(PLCZ1):c.563A>G (p.Tyr188Cys)	PIK3C2G	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 0 · 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
PLCZ1	Strong	Autosomal recessive	spermatogenic failure 17

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCZ1	HGNC:19218	ENSG00000139151	Q86YW0	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	gencc
PIK3C2G	HGNC:8973	ENSG00000139144	O75747	Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLCZ1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
PIK3C2G	Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma	Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCZ1	Other/Unknown	no		C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
PIK3C2G	Kinase	yes	2.7.1.137	C2_dom, PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
sperm	1
corpus epididymis	1
hair follicle	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCZ1	117	tissue_specific	marker	sperm, left testis, right testis
PIK3C2G	148	tissue_specific	marker	corpus epididymis, hair follicle, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLCZ1	1,183
PIK3C2G	929

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3C2G	O75747	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLCZ1	Q86YW0	92.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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 PIPs at the Golgi membrane	1	317.2×	0.007	PIK3C2G
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.007	PLCZ1
Synthesis of PIPs at the plasma membrane	1	105.7×	0.009	PIK3C2G

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of cytosolic calcium ion concentration involved in egg activation	1	8426.0×	0.001	PLCZ1
egg activation	1	4213.0×	0.001	PLCZ1
host-mediated perturbation of viral process	1	936.2×	0.004	PIK3C2G
phosphatidylinositol-3-phosphate biosynthetic process	1	648.1×	0.005	PIK3C2G
phosphatidylinositol-mediated signaling	1	351.1×	0.007	PIK3C2G
lipid catabolic process	1	122.1×	0.016	PLCZ1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.016	PIK3C2G
calcium ion transport	1	90.6×	0.017	PLCZ1
chemotaxis	1	68.0×	0.020	PIK3C2G
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.020	PLCZ1
cell migration	1	30.8×	0.035	PIK3C2G
intracellular signal transduction	1	19.1×	0.052	PLCZ1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
PIK3C2G	LAPATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3C2G	7	4
PLCZ1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LAPATINIB	4	PIK3C2G
MIDOSTAURIN	4	PIK3C2G
LESTAURTINIB	3	PIK3C2G
TG100-115	2	PIK3C2G
AZD-8154	2	PIK3C2G
PICTILISIB	2	PIK3C2G
SAR-260301	1	PIK3C2G

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3C2G	123	Binding:123
PLCZ1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3C2G	2.7.1.137, 2.7.1.154	phosphatidylinositol 3-kinase, phosphatidylinositol-4-phosphate 3-kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIK3C2G	123

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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)
LAPATINIB	4	PIK3C2G
MIDOSTAURIN	4	PIK3C2G
LESTAURTINIB	3	PIK3C2G
TG100-115	2	PIK3C2G
AZD-8154	2	PIK3C2G
PICTILISIB	2	PIK3C2G
SAR-260301	1	PIK3C2G

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3C2G
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PLCZ1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCZ1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.