PLCZ1

Summary

PLCZ1 (phospholipase C zeta 1, HGNC:19218) is a protein-coding gene on chromosome 12p12.3, encoding 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (Q86YW0). 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.

The protein encoded by this gene is a member of the phosphoinositide-specific phospholipase C family. Members in this family, classified into six isotypes that are tissue- and organ-specific, hydrolyze phosphatidylinositol 4,5-bisphosphate just before the phosphate group to yield diacylglycerol and inositol 1,4,5-trisphosphate. This protein localizes to the acrosome in spermatozoa and elicits Ca(2+) oscillations and egg activation during fertilization that leads to early embryonic development. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 89869 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 17 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 8 total
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_033123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19218
Approved symbol	PLCZ1
Name	phospholipase C zeta 1
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Aliases	NYD-SP27, PLCzeta, Czeta
Ensembl gene	ENSG00000139151
Ensembl biotype	protein_coding
OMIM	608075
Entrez	89869

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 5 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000266505, ENST00000318197, ENST00000534932, ENST00000535429, ENST00000536023, ENST00000538330, ENST00000539072, ENST00000539207, ENST00000539875, ENST00000540270, ENST00000540421, ENST00000540515, ENST00000541109, ENST00000541966, ENST00000542762, ENST00000543219, ENST00000543242, ENST00000544849, ENST00000545129, ENST00000648272

RefSeq mRNA: 3 — MANE Select: NM_033123 NM_001330769, NM_001330774, NM_033123

CCDS: CCDS81671, CCDS8680

Canonical transcript exons

ENST00000266505 — 15 exons

Exon	Start	End
ENSE00002319741	18737932	18738012
ENSE00003502556	18701692	18701776
ENSE00003509010	18694910	18695079
ENSE00003509210	18712842	18712986
ENSE00003560689	18688089	18688218
ENSE00003563485	18719431	18719632
ENSE00003606312	18684130	18684279
ENSE00003629112	18705166	18705315
ENSE00003630892	18737361	18737509
ENSE00003640816	18723311	18723542
ENSE00003641113	18699794	18699950
ENSE00003658065	18696150	18696266
ENSE00003680012	18736221	18736344
ENSE00003789205	18701501	18701568
ENSE00003891930	18683180	18683324

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 99.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0339 / max 34.1445, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129999	0.0339	3

Top tissues by expression

240 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.16	gold quality
left testis	UBERON:0004533	93.24	gold quality
right testis	UBERON:0004534	92.78	gold quality
testis	UBERON:0000473	90.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.81	gold quality
adult organism	UBERON:0007023	82.95	gold quality
secondary oocyte	CL:0000655	66.07	silver quality
skin of abdomen	UBERON:0001416	65.49	gold quality
skin of leg	UBERON:0001511	63.33	gold quality
body of stomach	UBERON:0001161	62.87	gold quality
zone of skin	UBERON:0000014	61.50	gold quality
stomach	UBERON:0000945	60.80	gold quality
right lobe of liver	UBERON:0001114	58.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	56.56	gold quality
buccal mucosa cell	CL:0002336	55.11	gold quality
fundus of stomach	UBERON:0001160	54.42	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
ileal mucosa	UBERON:0000331	54.18	silver quality
kidney epithelium	UBERON:0004819	53.93	gold quality
epithelial cell of pancreas	CL:0000083	53.83	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
pancreatic ductal cell	CL:0002079	53.20	silver quality
metanephros cortex	UBERON:0010533	52.94	gold quality
tibialis anterior	UBERON:0001385	51.91	silver quality
cardiac atrium	UBERON:0002081	51.85	gold quality
right atrium auricular region	UBERON:0006631	51.85	gold quality
gall bladder	UBERON:0002110	51.21	gold quality
liver	UBERON:0002107	50.32	gold quality
myocardium	UBERON:0002349	50.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.21
E-MTAB-6075	no	30.55

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• confirm the previously proposed inhibitory role of NYD-SP27 in the PLC pathway and demonstrate that the suppression of its expression could result in an enhancement of ATP-stimulated Ca(2+) dependent pancreatic anion secretion. (PMID:17196844)
• narrow spectrum of PLCZ1 activity indicates that it is modulated by tissue-restricted accessory factors (PMID:17933795)
• Human PLCzeta can readily activate mouse oocytes, however, effective development to blastocyst stages is only achieved within a specific window of hPLCzeta-luc protein expression levels. (PMID:18003622)
• All PLCZ1 proteins including fish could induce Ca(2+) oscillations in mouse eggs, but the activity was variable in the order of human » mouse > medaka » rat, estimated from minimal RNA concentration to induce Ca(2+) spikes. (PMID:18322275)
• Human sperm devoid of PLCZ1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development. (PMID:18924610)
• Male infertility-linked point mutation disrupts the Ca2+ oscillation-inducing and PIP(2) hydrolysis activity of sperm PLC gamma. (PMID:21204786)
• PLCzeta may have a role in sperm inducing oocyte activation after ICSI (PMID:21896550)
• a maternally inherited autosomal point mutation in human phospholipase C zeta (PLCzeta) leads to male infertility (PMID:22095789)
• Phospholipase C-zeta-induced Ca2+ oscillations cause coincident cytoplasmic movements in human oocytes that failed to fertilize after intracytoplasmic sperm injection. (PMID:22217962)
• PLCzeta is compartmentalized as part of the acrosome early in human and mouse spermiogenesis and is secreted during sperm maturation in the epididymis. (PMID:22428063)
• Loss-of-activity mutations in PLCzeta may contribute not only toward male infertility but also male subfertility in cases where PLCzeta is mutated on a single allele. (PMID:22633260)
• investigation of expression level and localization pattern of PLCZ1 in sperm from three infertile patients with globozoospermia (i.e., patients who exhibited abnormal sperm with round heads) [CASE REPORT] (PMID:22940771)
• Male infertility is associated with the aberrant expression, localisation, structure and function of PLCzeta in human sperm. [review] (PMID:23916605)
• PLCzeta may be a significant factor in human fertility with potential therapeutic capacity. [Review] (PMID:24157362)
• Human PLCzeta exhibits superior fertilization potency over mouse PLCzeta in triggering the Ca(2+) oscillations required for mammalian oocyte activation. (PMID:24478462)
• in patients with normal SA parameters but with repeated low fertilization or outright failed fertilization results after ICSI, abnormal PLCZ1 function should be considered as the underlying mechanism responsible for the failure of fertilization (PMID:24756570)
• Data suggest that PAWP (WW domain-binding protein 2-like) from sperm (rather than PLCZ [phospholipase C zeta] from sperm) acts as the ‘sperm factor’ within the egg at fertilization and is involved in ’egg activation’ and embryogenesis. [REVIEW] (PMID:25722320)
• I discuss the recent advances in our knowledge of the intriguing biochemical and physiological properties of sperm PLCz and postulate potential roles for PLCz in terms of clinical diagnosis and therapy for certain forms of male infertility (PMID:26009178)
• Study further supports the fundamental role of PLCzeta in the oocyte activation process. (PMID:26054556)
• Human PLCzeta elicited the characteristic Ca(2+) oscillations present at mammalian fertilization, which produced oocyte activation and embryo development. (PMID:26116451)
• Phospholipase C-zeta deficiency is associated with repetitive oocyte fertilization failure during ovarian stimulation for in vitro fertilization. (PMID:26174123)
• The role of the PLCZ1 protein in male infertility, and its expression regulation and therapeutic potential have been discussed. (Review) (PMID:26700242)
• In male infertility, the absence of PLCZ1 alone is sufficient to prevent oocyte activation irrespective of the presence of PAWP. (PMID:26721930)
• we evaluate sperm motility and the proportion of sperm expressing PLC zeta in 71 males (22-54 years; 44 fertile controls and 27 infertile patients), along with total levels and localisation patterns of PLC zeta within the sperm head. (PMID:27270687)
• The findings of the present study illustrate that one of the etiologies of reduced fertility associated with varicocele is the low expression of PLCzeta (PMID:27612872)
• The value of PAWP and PLCzeta as indicators of sperm quality was studied. (PMID:28076980)
• The findings highlight the importance of PLCzeta at fertilization and the vital role of the C2 domain in PLCzeta function, possibly due to its novel binding characteristics. (PMID:28270562)
• findings suggest that human PLCZ1 RNA is a better therapeutic agent to rescue human oocytes from failed activation, leading to normal and efficient development. (PMID:28320563)
• PLCzeta and PAWP impairments may be one of the possible etiologies of decreased fertility in Oligoasthenoteratozoospermia (PMID:28954204)
• latest developments that have begun to unravel the vital role of PLCzeta at mammalian fertilisation and decipher its unique mechanism of action within the fertilising egg. (PMID:29061915)
• Phospholipase C zeta and calcium oscillations at fertilization. (PMID:29108881)
• Low PLCZ1 expression is associated with globozoospermia with DPY19L2 deletion. (PMID:29339016)
• Novel phospholipase C zeta 1 mutations associated with fertilization failures after ICSI. (PMID:31347677)
• Novel homozygous variations in PLCZ1 lead to poor or failed fertilization characterized by abnormal localization patterns of PLCzeta in sperm. (PMID:31463947)
• The alteration of PLCzeta protein expression in unexplained infertile and asthenoteratozoospermic patients: A potential effect on sperm fertilization ability. (PMID:31736165)
• The identification of novel mutations in PLCZ1 responsible for human fertilization failure and a therapeutic intervention by artificial oocyte activation. (PMID:31953539)
• Novel mutations in PLCZ1 cause male infertility due to fertilization failure or poor fertilization. (PMID:32048714)
• A novel homozygous mutation of phospholipase C zeta leading to defective human oocyte activation and fertilization failure. (PMID:32142120)
• A homozygous nonsense mutation of PLCZ1 cause male infertility with oocyte activation deficiency. (PMID:32146562)
• Increasing associations between defects in phospholipase C zeta and conditions of male infertility: not just ICSI failure? (PMID:32285298)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Plcz1	ENSMUSG00000030230
rattus_norvegicus	Plcz1	ENSRNOG00000008514
drosophila_melanogaster	sl	FBGN0003416
drosophila_melanogaster	Plc21C	FBGN0004611
caenorhabditis_elegans		WBGENE00004038
caenorhabditis_elegans		WBGENE00004039
caenorhabditis_elegans		WBGENE00004045

Paralogs (14): PLCB4 (ENSG00000101333), PLCH1 (ENSG00000114805), PLCD4 (ENSG00000115556), PLCL1 (ENSG00000115896), PLCG1 (ENSG00000124181), PLCB2 (ENSG00000137841), PLCE1 (ENSG00000138193), PLCH2 (ENSG00000149527), PLCB3 (ENSG00000149782), PLCL2 (ENSG00000154822), PLCD3 (ENSG00000161714), PLCB1 (ENSG00000182621), PLCD1 (ENSG00000187091), PLCG2 (ENSG00000197943)

Protein

Protein identifiers

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 — Q86YW0 (reviewed: Q86YW0)

Alternative names: Phosphoinositide phospholipase C-zeta-1, Phospholipase C-zeta-1, Testis-development protein NYD-SP27

All UniProt accessions (14): Q86YW0, A0A140VJR9, A0A3B3ISW9, F5GYE4, F5GZK3, F5H2D7, F5H3L4, F5H474, F5H828, H0YFH9, H0YGH7, H0YGY7, H0YH40, Q8N7S5

UniProt curated annotations — full annotation on UniProt →

Function. 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. In vitro, hydrolyzes PtdIns(4,5)P2 in a Ca(2+)-dependent manner. Triggers intracellular Ca(2+) oscillations in oocytes solely during M phase and is involved in inducing oocyte activation and initiating embryonic development up to the blastocyst stage. Is therefore a strong candidate for the egg-activating soluble sperm factor that is transferred from the sperm into the egg cytoplasm following gamete membrane fusion. May exert an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function.

Subunit / interactions. Interacts via its C2 domain with PtdIns(3)P and, to a lesser extent, PtdIns(5)P in vitro.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed specifically in testis and sperm. Weakly expressed in pancreatic-duct cells. Up-regulated in pancreatic-duct cells from patients with cystic fibrosis.

Disease relevance. Spermatogenic failure 17 (SPGF17) [MIM:617214] An autosomal recessive infertility disorder due to failure of oocyte activation and fertilization by sperm that otherwise exhibits normal morphology. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The EF-hand and C2 domains are essential for triggering Ca(2+) oscillating activity and the regulation of PLCZ1 enzyme activity. The X-Y linker region between PI-PLC X-box and Y-box domains may be a target for proteolysis and may play an important regulatory role during fertilization.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86YW0-1	1	yes
Q86YW0-2	2
Q86YW0-3	3

RefSeq proteins (3): NP_001317698, NP_001317703, NP_149114* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000909	PLipase_C_PInositol-sp_X_dom	Domain
IPR001192	PI-PLC_fam	Family
IPR001711	PLipase_C_Pinositol-sp_Y	Domain
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR015359	PLC_EF-hand-like	Domain
IPR017946	PLC-like_Pdiesterase_TIM-brl	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily

Pfam: PF00168, PF00387, PF00388, PF09279

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = 1D-myo-inositol 1,4,5-trisphosphate + a 1,2-diacyl-sn-glycerol + H(+) (RHEA:33179)

UniProt features (17 total): sequence variant 5, domain 4, sequence conflict 2, active site 2, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YW0-F1	92.21	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 170; 215

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol

MSigDB gene sets: 74 (showing top): GOBP_SINGLE_FERTILIZATION, KORKOLA_CHORIOCARCINOMA_DN, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, KORKOLA_EMBRYONAL_CARCINOMA_DN, GOBP_LIPID_METABOLIC_PROCESS, NKX22_01, AFFAR_YY1_TARGETS_UP, GOBP_FERTILIZATION, GOBP_LIPID_CATABOLIC_PROCESS, KEGG_OOCYTE_MEIOSIS, GOCC_PRONUCLEUS, GOCC_NUCLEOLUS, GOMF_PHOSPHATIDYLINOSITOL_5_PHOSPHATE_BINDING, GOMF_PHOSPHATIDYLINOSITOL_4_5_BISPHOSPHATE_BINDING

GO Biological Process (9): calcium ion transport (GO:0006816), positive regulation of cytosolic calcium ion concentration (GO:0007204), egg activation (GO:0007343), lipid catabolic process (GO:0016042), intracellular signal transduction (GO:0035556), positive regulation of cytosolic calcium ion concentration involved in egg activation (GO:0060470), lipid metabolic process (GO:0006629), signal transduction (GO:0007165), single fertilization (GO:0007338)

GO Molecular Function (8): phosphatidylinositol-4,5-bisphosphate phospholipase C activity (GO:0004435), calcium ion binding (GO:0005509), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-5-phosphate binding (GO:0010314), phosphatidylinositol-3-phosphate binding (GO:0032266), C-type glycerophospholipase activity (GO:0004629), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), pronucleus (GO:0045120), perinuclear region of cytoplasm (GO:0048471), sperm head (GO:0061827), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Inositol phosphate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
phosphatidylinositol phosphate binding	3
intracellular anatomical structure	2
nuclear lumen	2
cytoplasm	2
metal ion transport	1
regulation of biological quality	1
cell activation	1
single fertilization	1
lipid metabolic process	1
catabolic process	1
signal transduction	1
positive regulation of cytosolic calcium ion concentration	1
egg activation	1
primary metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
fertilization	1
C-type glycerophospholipase activity	1
metal ion binding	1
phosphatidylinositol bisphosphate binding	1
anion binding	1
glycerophospholipase activity	1
phosphoric diester hydrolase activity	1
phosphoric ester hydrolase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
nucleus	1

Protein interactions and networks

STRING

1152 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLCZ1	WBP2NL	Q6ICG8	808
PLCZ1	PLEK2	Q9NYT0	694
PLCZ1	PLEK	P08567	692
PLCZ1	CAPZA3	Q96KX2	625
PLCZ1	SPATA16	Q9BXB7	612
PLCZ1	DPY19L2	Q6NUT2	595
PLCZ1	ACTL7A	Q9Y615	584
PLCZ1	SPAG9	O60271	580
PLCZ1	WBP2	Q969T9	574
PLCZ1	IZUMO1	Q8IYV9	573
PLCZ1	FAM209A	Q5JX71	539
PLCZ1	ITPR1	Q14643	519
PLCZ1	TSSK6	Q9BXA6	517
PLCZ1	SPATA31G1	Q5VYM1	513
PLCZ1	GARIN2	Q8N9W8	507

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PLCZ1	NPM1	psi-mi:“MI:0915”(physical association)	0.400
PLCZ1	ACTC1	psi-mi:“MI:0915”(physical association)	0.400
PLCZ1	PRKCSH	psi-mi:“MI:0915”(physical association)	0.400
PLCZ1	ALOX12B	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): KLK7 (Affinity Capture-MS), CST6 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), HAL (Affinity Capture-MS), HBD (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), KLK7 (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), CST6 (Affinity Capture-MS), ECM1 (Affinity Capture-MS), HAL (Affinity Capture-MS), PLCZ1 (Synthetic Lethality), PLCZ1 (Proximity Label-MS), PLCZ1 (Proximity Label-MS)

ESM2 similar proteins: A2AP18, A3KGF7, A5D6R3, A6NHC0, O00329, O14815, O35904, O35920, O75038, O89040, P08487, P10686, P10688, P10895, P16885, P19174, P21671, P24135, P51178, Q00722, Q15111, Q1RML2, Q2VRL0, Q32NH8, Q39032, Q3USB7, Q4KWH5, Q4KWH8, Q4R6L3, Q4V8Q1, Q56W08, Q5FX52, Q5RET0, Q62077, Q62688, Q62711, Q6J756, Q78EJ9, Q7YRU3, Q86YW0

Diamond homologs: A2AP18, A3KGF7, A5D6R3, G5EBH0, G5EFI8, O75038, O89040, P10687, P10688, P10894, P10895, P21671, P25455, P51178, P51432, Q00722, Q01970, Q07722, Q15111, Q15147, Q1RML2, Q2VRL0, Q32NH8, Q3USB7, Q4KWH5, Q4KWH8, Q4R6L3, Q5FX52, Q5RET0, Q62688, Q62711, Q6NMA7, Q7YRU3, Q86YW0, Q8K2J0, Q8K394, Q8K3R3, Q8K4D7, Q8K4S1, Q8L706

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

8 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2701 predictions. Top by Δscore:

Variant	Effect	Δscore
12:18696267:C:CC	acceptor_gain	1.0000
12:18702165:T:TC	acceptor_gain	1.0000
12:18694908:AC:A	donor_gain	0.9900
12:18694909:CC:C	donor_gain	0.9900
12:18695077:CCA:C	acceptor_gain	0.9900
12:18695078:CAC:C	acceptor_gain	0.9900
12:18695080:C:CC	acceptor_gain	0.9900
12:18696263:TGGA:T	acceptor_gain	0.9900
12:18702161:A:T	acceptor_gain	0.9900
12:18702163:CAT:C	acceptor_gain	0.9900
12:18702164:A:C	acceptor_gain	0.9900
12:18702165:T:C	acceptor_gain	0.9900
12:18712987:C:CC	acceptor_gain	0.9900
12:18723572:T:TC	acceptor_gain	0.9900
12:18724931:TTCAA:T	donor_gain	0.9900
12:18736342:CA:C	acceptor_gain	0.9900
12:18736343:A:C	acceptor_gain	0.9900
12:18737845:T:TA	donor_gain	0.9900
12:18694971:CT:C	donor_gain	0.9800
12:18695010:C:CT	donor_gain	0.9800
12:18695076:GCCA:G	acceptor_gain	0.9800
12:18695077:CCAC:C	acceptor_gain	0.9800
12:18695078:CA:C	acceptor_gain	0.9800
12:18696159:A:AT	donor_gain	0.9800
12:18699948:GGTC:G	acceptor_gain	0.9800
12:18702160:C:CT	acceptor_gain	0.9800
12:18712985:CA:C	acceptor_gain	0.9800
12:18723568:CACAT:C	acceptor_gain	0.9800
12:18723570:CAT:C	acceptor_gain	0.9800
12:18723578:G:GC	acceptor_gain	0.9800

AlphaMissense

4037 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:18684213:C:G	R553P	0.999
12:18695069:A:C	N434K	0.999
12:18695069:A:T	N434K	0.999
12:18696171:A:G	W424R	0.999
12:18696171:A:T	W424R	0.999
12:18696190:A:C	N417K	0.999
12:18696190:A:T	N417K	0.999
12:18712966:C:G	R197P	0.998
12:18712967:G:T	R197S	0.998
12:18719492:G:C	H170D	0.998
12:18684265:A:G	W536R	0.997
12:18684265:A:T	W536R	0.997
12:18694991:T:A	K460N	0.997
12:18694991:T:G	K460N	0.997
12:18695002:A:C	Y457D	0.997
12:18695004:C:T	G456E	0.997
12:18695015:A:C	N452K	0.997
12:18695015:A:T	N452K	0.997
12:18696169:C:A	W424C	0.997
12:18696169:C:G	W424C	0.997
12:18701754:A:T	V296D	0.997
12:18701772:A:G	L290P	0.997
12:18705274:G:C	C252W	0.997
12:18719487:G:C	N171K	0.997
12:18719487:G:T	N171K	0.997
12:18719510:A:C	Y164D	0.997
12:18695024:A:C	F449L	0.996
12:18695024:A:T	F449L	0.996
12:18695026:A:G	F449L	0.996
12:18695071:T:C	N434D	0.996

dbSNP variants (sampled 300 via entrez): RS1000017843 (12:18660102 G>A), RS1000040908 (12:18694667 G>C), RS1000042639 (12:18672324 C>A,G,T), RS1000067427 (12:18667023 G>A,T), RS1000099842 (12:18700850 T>C), RS1000110979 (12:18670901 G>A), RS1000147522 (12:18689305 A>G), RS1000194050 (12:18661070 A>T), RS1000235488 (12:18707766 T>C), RS1000345035 (12:18661728 C>A), RS1000392258 (12:18694945 T>C), RS1000399767 (12:18711686 G>T), RS1000411207 (12:18655388 G>A), RS1000411878 (12:18672656 C>G), RS1000423921 (12:18736114 T>A,C,G)

Disease associations

OMIM: gene MIM:608075 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 17	Strong	Autosomal recessive

Mondo (1): spermatogenic failure 17 (MONDO:0014970)

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003518_20	Daytime sleep phenotypes	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6195766 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Phosphoinositide-specific phospholipase C

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
tianma gouteng yin	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Silicon Dioxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6193902	Binding	Binding affinity to human PLCZ1 using Nuvisan Phospholipase C panel (PLCZ1)	Data for DCP probe BAY-439

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.