ZP1

Summary

ZP1 (zona pellucida glycoprotein 1, HGNC:13187) is a protein-coding gene on chromosome 11q12.2, encoding Zona pellucida sperm-binding protein 1 (P60852). Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.

The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by this gene ensures the structural integrity of the zona pellucida. Mutations in this gene are a cause of oocyte maturation defect and infertility.

Source: NCBI Gene 22917 — RefSeq curated summary.

At a glance

• Gene–disease (curated): female infertility due to zona pellucida defect (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 154 total — 11 pathogenic, 5 likely-pathogenic
• GTEx eGene: eQTL in 9 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 4
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.03 (unconstrained)
• MANE Select transcript: NM_207341

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13187
Approved symbol	ZP1
Name	zona pellucida glycoprotein 1
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	ZPB1
Ensembl gene	ENSG00000149506
Ensembl biotype	protein_coding
OMIM	195000
Entrez	22917

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 1 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000278853

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 1, TSL 4: 1, TSL 5: 1

ENST00000278853, ENST00000537203, ENST00000540908, ENST00000542971, ENST00000543020

RefSeq mRNA: 3 — MANE Select: NM_207341 NM_001391943, NM_001391944, NM_207341

CCDS: CCDS31572

Canonical transcript exons

ENST00000278853 — 12 exons

Exon	Start	End
ENSE00000990965	60869145	60869266
ENSE00000990967	60869537	60869900
ENSE00001304028	60867542	60867757
ENSE00001305834	60870957	60871144
ENSE00003459108	60874933	60875014
ENSE00003508022	60870332	60870475
ENSE00003524266	60873634	60873775
ENSE00003553573	60873375	60873564
ENSE00003573293	60875514	60875687
ENSE00003593638	60873162	60873289
ENSE00003610586	60875129	60875248
ENSE00003653412	60871217	60871314

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 96.41.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3623 / max 25.4543, expressed in 161 samples.

Highest expression (Bgee): oocyte, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, pituitary gland, adenohypophysis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ZP1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Pituitary	eqtl	4.9e-12	-0.39	11:60935604:C:T
Brain Cerebellar Hemisphere	eqtl	1.8e-11	-0.49	11:60940424:C:G
Brain Cerebellum	eqtl	1.8e-10	-0.54	11:60940424:C:G
Skin Sun Exposed Lower leg	eqtl	5.6e-03	+0.56	11:60436399:C:T
Artery Tibial	eqtl	6.7e-03	-0.49	11:61580265:A:G
Artery Coronary	eqtl	1.2e-02	-1.49	11:60983394:T:C
Esophagus Mucosa	eqtl	1.9e-02	-0.66	11:60854923:G:A
Brain Caudate basal ganglia	eqtl	3.3e-02	+0.31	11:60868754:T:C
Nerve Tibial	eqtl	3.9e-02	+0.20	11:60811387:C:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
114511	0.1791	82
114512	0.1171	46
114513	0.0491	23
114509	0.0127	5
114510	0.0043	3

Top tissues by expression

showing 100 of 245 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	96.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.86	gold quality
secondary oocyte	CL:0000655	86.98	gold quality
pituitary gland	UBERON:0000007	81.91	gold quality
adenohypophysis	UBERON:0002196	80.17	gold quality
left testis	UBERON:0004533	71.53	gold quality
right testis	UBERON:0004534	70.63	gold quality
testis	UBERON:0000473	69.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.25	gold quality
omental fat pad	UBERON:0010414	68.06	gold quality
peritoneum	UBERON:0002358	68.02	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.49	gold quality
cerebellar hemisphere	UBERON:0002245	65.41	gold quality
cerebellar cortex	UBERON:0002129	65.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	64.97	gold quality
cerebellum	UBERON:0002037	64.59	gold quality
subcutaneous adipose tissue	UBERON:0002190	64.45	gold quality
adipose tissue	UBERON:0001013	63.32	gold quality
granulocyte	CL:0000094	61.39	gold quality
islet of Langerhans	UBERON:0000006	61.07	gold quality
adrenal tissue	UBERON:0018303	60.92	gold quality
deltoid	UBERON:0001476	60.85	gold quality
parotid gland	UBERON:0001831	60.26	gold quality
buccal mucosa cell	CL:0002336	60.04	gold quality
body of stomach	UBERON:0001161	60.04	gold quality
nasal cavity epithelium	UBERON:0005384	59.96	gold quality
tendon of biceps brachii	UBERON:0008188	59.63	gold quality
right adrenal gland	UBERON:0001233	59.13	gold quality
upper leg skin	UBERON:0004262	58.91	silver quality
transverse colon	UBERON:0001157	58.86	gold quality
lower esophagus mucosa	UBERON:0035834	58.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	58.45	gold quality
mucosa of transverse colon	UBERON:0004991	58.43	gold quality
sperm	CL:0000019	58.09	gold quality
vena cava	UBERON:0004087	57.91	gold quality
pancreatic ductal cell	CL:0002079	57.68	silver quality
right adrenal gland cortex	UBERON:0035827	57.61	gold quality
myocardium	UBERON:0002349	56.89	gold quality
fundus of stomach	UBERON:0001160	56.86	gold quality
gastrocnemius	UBERON:0001388	56.77	gold quality
putamen	UBERON:0001874	56.39	gold quality
small intestine	UBERON:0002108	56.35	gold quality
upper arm skin	UBERON:0004263	56.20	gold quality
heart left ventricle	UBERON:0002084	56.18	gold quality
cardiac ventricle	UBERON:0002082	56.12	gold quality
stomach	UBERON:0000945	55.91	gold quality
left adrenal gland	UBERON:0001234	55.86	gold quality
ectocervix	UBERON:0012249	55.84	gold quality
heart right ventricle	UBERON:0002080	55.80	gold quality
cerebellar vermis	UBERON:0004720	55.48	gold quality
muscle of leg	UBERON:0001383	55.44	gold quality
nucleus accumbens	UBERON:0001882	55.32	gold quality
muscle tissue	UBERON:0002385	55.24	gold quality
skeletal muscle tissue	UBERON:0001134	55.06	silver quality
ileal mucosa	UBERON:0000331	54.91	silver quality
saphenous vein	UBERON:0007318	54.69	gold quality
adrenal gland	UBERON:0002369	54.51	gold quality
epithelial cell of pancreas	CL:0000083	54.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
thymus	UBERON:0002370	54.33	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
corpus epididymis	UBERON:0004359	54.13	gold quality
decidua	UBERON:0002450	54.12	gold quality
adrenal cortex	UBERON:0001235	54.10	gold quality
pharyngeal mucosa	UBERON:0000355	54.01	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
pons	UBERON:0000988	53.74	gold quality
colonic epithelium	UBERON:0000397	53.67	silver quality
pericardium	UBERON:0002407	53.62	gold quality
substantia nigra pars compacta	UBERON:0001965	53.41	gold quality
cauda epididymis	UBERON:0004360	53.33	gold quality
left adrenal gland cortex	UBERON:0035825	53.32	gold quality
trachea	UBERON:0003126	53.20	gold quality
caput epididymis	UBERON:0004358	53.15	gold quality
layer of synovial tissue	UBERON:0007616	53.15	gold quality
intestine	UBERON:0000160	53.13	gold quality
quadriceps femoris	UBERON:0001377	53.02	gold quality
colon	UBERON:0001155	52.99	gold quality
mucosa of sigmoid colon	UBERON:0004993	52.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	52.85	gold quality
cartilage tissue	UBERON:0002418	52.84	gold quality
biceps brachii	UBERON:0001507	52.82	gold quality
trigeminal ganglion	UBERON:0001675	52.80	gold quality
brain	UBERON:0000955	52.74	gold quality
nipple	UBERON:0002030	52.71	gold quality
superior surface of tongue	UBERON:0007371	52.63	gold quality
dorsal root ganglion	UBERON:0000044	52.60	gold quality
large intestine	UBERON:0000059	52.59	gold quality
inferior vagus X ganglion	UBERON:0005363	52.34	gold quality
trabecular bone tissue	UBERON:0002483	52.30	gold quality
penis	UBERON:0000989	52.29	gold quality
medulla oblongata	UBERON:0001896	52.29	gold quality
pylorus	UBERON:0001166	52.13	gold quality
medial globus pallidus	UBERON:0002477	52.13	gold quality
globus pallidus	UBERON:0001875	52.06	gold quality
synovial joint	UBERON:0002217	51.99	gold quality
caudate nucleus	UBERON:0001873	51.90	gold quality
superior vestibular nucleus	UBERON:0007227	51.89	gold quality
ventral tegmental area	UBERON:0002691	51.87	gold quality
left uterine tube	UBERON:0001303	51.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25

HPA expression

RNA tissue specificity: Not detected

19 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Basal ganglia	tissue	0.8
Caudate putamen	tissue	0.8
Retrosplenial cortex	tissue	0.8
Pituitary gland	tissue	0.5
Putamen	tissue	0.4
Medulla oblongata	tissue	0.3
Thymus	tissue	0.3
Ventral forebrain	tissue	0.3
Epididymis	tissue	0.2
Nucleus accumbens	tissue	0.2
Spinal cord	tissue	0.2
Hippocampus	tissue	0.2
Postcentral gyrus	tissue	0.2
Ovary	tissue	0.1
Parathyroid gland	tissue	0.1
Hypothalamus	tissue	0.1
Substantia nigra	tissue	0.1
Locus coeruleus	tissue	0.1
Prostate	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 170; highest nTPM — Area striata (0.7), Supramarginal gyrus (0.7), Inferior parietal lobule (0.6), Parietal operculum (0.6), Precentral gyrus (0.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FIGLA, SOHLH1

Functional genomics

gnomAD constraint: pLI 2.34e-17, LOEUF 1.03, missense Z 0.966 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000278853 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 20)

• ZP proteins were detected in both the oocyte and the granulosa cells as early as the primordial follicle stage in the human. The detection of ZP proteins in the quiescent primordial follicle suggests that these proteins have been present since oogenesis. (PMID:18033806)
• ZP1 binds to capacitated spermatozoa and induces acrosomal exocytosis. (PMID:20504872)
• The ‘ZP domain’ module of human ZP1 has functional activity and may have a role during fertilization in humans. (PMID:20831819)
• observed sequence variations in exons of ZP1 gene in women with infertility of unknown origin who exhibit abnormal zona pellucida; sperm-ovum interactions appear relatively normal in these patients [CASE REPORTS] (PMID:22889493)
• this study identified a homozygous frameshift mutation in ZP1 in six family members with a form of infertility with an autosomal recessive mode of inheritance. (PMID:24670168)
• Our findings presented compound heterozygous mutations in ZP1 associated with Empty follicle syndrome (EFS) and abnormal oocytes and provided further new evidence for the genetic basis of EFS and support for the genetic diagnosis of infertile individuals (PMID:30778819)
• Mutations in ZP1, ZP2, and ZP3 might affect the corresponding protein expression, secretion, and interaction, thus providing a mechanistic explanation for the phenotypes for female infertility. (PMID:30810869)
• Study report a characterization of ZP1 proteins carrying mutations from infertile patients, which suggests that, in human, filament cross-linking by ZP1 is crucial to form a stable zona pellucida (ZP) and map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. (PMID:31300655)
• ZP1 mutations are associated with empty follicle syndrome: evidence for the existence of an intact oocyte and a zona pellucida in follicles up to the early antral stage. A case report. (PMID:31734689)
• Novel ZP1 pathogenic variants identified in an infertile patient and a successful live birth following ICSI treatment. (PMID:31909477)
• Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect. (PMID:32244758)
• Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome. (PMID:32556881)
• Zona Pellucida Proteins, Fibrils, and Matrix. (PMID:32569527)
• Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human. (PMID:32573113)
• Novel mutations in ZP1 and ZP2 cause primary infertility due to empty follicle syndrome and abnormal zona pellucida. (PMID:32829425)
• Novel mutations in ZP1: Expanding the mutational spectrum associated with empty follicle syndrome in infertile women. (PMID:33423275)
• A novel homozygous nonsense mutation in zona pellucida 1 (ZP1) causes human female empty follicle syndrome. (PMID:33665726)
• A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females. (PMID:35460069)
• A Novel Homozygous Nonsense Mutation in ZP1 Causes Female Infertility due to Empty Follicle Syndrome. (PMID:35773450)
• Novel variants in ZP1, ZP2 and ZP3 associated with empty follicle syndrome and abnormal zona pellucida. (PMID:36931917)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zpax4	ENSDARG00000079034
mus_musculus	Zp1	ENSMUSG00000024734
rattus_norvegicus	Zp1	ENSRNOG00000020907

Paralogs (4): ZP2 (ENSG00000103310), ZP4 (ENSG00000116996), QRICH2 (ENSG00000129646), C16orf96 (ENSG00000205832)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103073) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal ovarian folliculogenesis	1
abnormal reproductive system physiology	1
reduced female fertility	1
decreased litter size	1
abnormal zona pellucida morphology	1
abnormal granulosa cell morphology	1
thin zona pellucida	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca radiata	O77726	94.2%	Diamond
Canis lupus familiaris	P47983	83.0%	Diamond
Felis catus	P47984	83.0%	Diamond
Sus scrofa	P42099	78.0%	Diamond
Bos taurus	Q9BH10	78.0%	Diamond
Oryctolagus cuniculus	Q00193	69.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PTGDR2	protein-coding	11251
CCDC86-AS1	ncRNA	127138859
MS4A15	protein-coding	219995
MS4A10	protein-coding	341116
MS4A18	protein-coding	728588
CCDC86	protein-coding	79080
TMEM109-DT	ncRNA	105369323
PRPF19	protein-coding	27339
TMEM109	protein-coding	79073
PRPF19-DT	ncRNA	107984333

Protein

Protein identifiers

Zona pellucida sperm-binding protein 1 — P60852 (reviewed: P60852)

Alternative names: Zona pellucida glycoprotein 1

All UniProt accessions (3): P60852, H0YG11, V9HWI9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy. The zona pellucida is composed of 3 to 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP1 ensures the structural integrity of the zona pellucida.

Subunit / interactions. Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers. Interacts with ZP3.

Subcellular location. Zona pellucida Cell membrane.

Tissue specificity. Expressed in oocytes (at protein level).

Post-translational modifications. Proteolytically cleaved before the transmembrane segment to yield the secreted ectodomain incorporated in the zona pellucida. O-glycosylated.

Disease relevance. Oocyte/zygote/embryo maturation arrest 1 (OZEMA1) [MIM:615774] An autosomal recessive infertility disorder caused by defective oocyte maturation that results in abnormal eggs lacking a zona pellucida. Affected females have normal menstrual cycles and sex hormone levels, no obstruction in the fallopian tubes or abnormalities of the uterus or adnexa. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ZP domain is involved in the polymerization of the ZP proteins to form the zona pellucida.

Similarity. Belongs to the ZP domain family. ZPB subfamily.

RefSeq proteins (3): NP_001378872, NP_001378873, NP_997224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000519	P_trefoil_dom	Domain
IPR001507	ZP_dom	Domain
IPR017957	P_trefoil_CS	Conserved_site
IPR017977	ZP_dom_CS	Conserved_site
IPR042235	ZP-C_dom	Homologous_superfamily
IPR044913	P_trefoil_dom_sf	Homologous_superfamily
IPR048290	ZP_chr	Domain
IPR051148	Zona_Pellucida_Domain_gp	Family
IPR054554	ZP1/4_Ig-like	Domain
IPR055355	ZP-C	Domain
IPR055356	ZP-N	Domain

Pfam: PF00100, PF22821, PF23344

UniProt features (21 total): glycosylation site 4, disulfide bond 4, chain 2, region of interest 2, topological domain 2, domain 2, signal peptide 1, compositionally biased region 1, sequence variant 1, propeptide 1, transmembrane region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60852-F1	73.67	0.38

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted secreted proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Functional residue map

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

Disulfide bonds (4)

Type	Positions
Disulfide bond	236–261, 245–260, 255–270, 457–478

Glycosylation sites (4)

Type	Positions
N-linked (glcnac…) asparagine	76, 379, 561, 596

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-2534343	Interaction With Cumulus Cells And The Zona Pellucida	curated
R-HSA-1187000	Fertilization	—
R-HSA-1474165	Reproduction	—

MSigDB gene sets: 76 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, SP3_Q3, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, TGCTGAY_UNKNOWN, GOBP_SPERM_EGG_RECOGNITION, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, RFX1_02, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, TGTYNNNNNRGCARM_UNKNOWN, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, MATZUK_FERTILIZATION, HEB_Q6, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (3): binding of sperm to zona pellucida (GO:0007339), prevention of polyspermy (GO:0060468), single fertilization (GO:0007338)

GO Molecular Function (3): acrosin binding (GO:0032190), structural constituent of egg coat (GO:0035804), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), plasma membrane (GO:0005886), egg coat (GO:0035805), extracellular matrix (GO:0031012)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Fertilization	1
Reproduction	1

GO top-level categories

13 GO namespaces:

Category	Terms
sperm-egg recognition	1
egg activation	1
negative regulation of fertilization	1
fertilization	1
enzyme binding	1
extracellular matrix structural constituent	1
egg coat	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1
specialized extracellular matrix	1
external encapsulating structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
egg coat	CC	direct assay

Protein interactions and networks

STRING

showing 16 of 592 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZP1	ZP3	P21754	987
ZP1	GDF9	O60383	779
ZP1	FIGLA	Q6QHK4	724
ZP1	MMUT	P22033	671
ZP1	ZP2	Q05996	666
ZP1	BMP15	O95972	626
ZP1	IZUMO1	Q8IYV9	625
ZP1	ASTL	Q6HA08	621
ZP1	NOBOX	O60393	612
ZP1	NLRP5	P59047	547
ZP1	H1-8	Q8IZA3	546
ZP1	OOSP1	A8MZH6	540
ZP1	SPESP1	Q6UW49	521
ZP1	ZAR1	Q86SH2	519
ZP1	DAZL	Q92904	498
ZP1	PATL2	C9JE40	498

IntAct

Human interaction partners of ZP1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ZP3	association	0.350	2

BioGRID (2 interactions; top human partners by supporting records): SPPL3 (Positive Genetic), SRGN (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
SOHLH1	“up-regulates quantity by expression”	ZP1	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for ZP1: 154 ClinVar records (16 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	5
Uncertain significance	115
Likely benign	12
Benign	8

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 16 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
812693	NM_207341.4(ZP1):c.1168del (p.Ile390fs)	Pathogenic	criteria provided, single submitter	3
689404	NM_207341.4(ZP1):c.1708G>A (p.Val570Met)	Pathogenic	criteria provided, single submitter	2
3353935	NM_207341.4(ZP1):c.670C>T (p.Arg224Ter)	Pathogenic	criteria provided, single submitter	2
695115	NM_207341.4(ZP1):c.769C>T (p.Gln257Ter)	Pathogenic	criteria provided, single submitter	1
2065331	NM_207341.4(ZP1):c.628C>T (p.Gln210Ter)	Pathogenic	criteria provided, single submitter	1
3382275	NM_207341.4(ZP1):c.1129_1130del (p.Val377fs)	Pathogenic	criteria provided, single submitter	1
3383023	NM_207341.4(ZP1):c.1602C>A (p.Cys534Ter)	Pathogenic	criteria provided, single submitter	1
3780815	NM_207341.4(ZP1):c.874C>T (p.Gln292Ter)	Pathogenic	criteria provided, single submitter	1
4850340	NM_207341.4(ZP1):c.217_221del (p.Asp73fs)	Likely pathogenic	criteria provided, single submitter	1
4855416	NM_207341.4(ZP1):c.1660C>T (p.Arg554Ter)	Likely pathogenic	criteria provided, single submitter	1
4883139	NM_207341.4(ZP1):c.1278T>G (p.Tyr426Ter)	Likely pathogenic	criteria provided, single submitter	1
127200	NM_207341.4(ZP1):c.1169_1176del (p.Ile390fs)	Pathogenic	no assertion criteria provided	1
689405	NM_207341.4(ZP1):c.1430+1G>T	Pathogenic	no assertion criteria provided	1
689406	NM_207341.4(ZP1):c.1775-8T>C	Pathogenic	no assertion criteria provided	1
3347218	NM_207341.4(ZP1):c.1015-1G>A	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ZP1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 781):

Position(s)	Effect	Δscore	Sites
11:60871321	donor_gain	1.0000
11:60873140	acceptor_gain	1.0000
11:60873146	acceptor_gain	1.0000
11:60873153	acceptor_gain	1.0000
11:60873290–60873291	donor_loss	1.0000	3
11:60873373	acceptor_loss	1.0000
11:60869140	acceptor_gain	0.9900
11:60869143–60869144	acceptor_loss	0.9900	6
11:60869267–60869268	donor_loss	0.9900	6
11:60870330–60870331	acceptor_loss	0.9900	6

AlphaMissense

669 missense substitutions predicted likely pathogenic (of 4,114 scored), across 195 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F505	8	0.939	0.991
D66	8	0.933	0.982
F510	8	0.931	0.992
D483	8	0.864	0.924
F578	8	0.845	0.956
C529	7	0.961	0.980
F417	7	0.959	0.991
C80	7	0.952	0.977
C457	7	0.942	0.977
C101	7	0.933	0.972
C135	7	0.928	0.967
F68	7	0.914	0.976
F72	7	0.914	0.974
C43	7	0.905	0.945
C77	7	0.903	0.945
F62	7	0.901	0.980
C376	7	0.897	0.946
C478	7	0.897	0.961
W471	7	0.889	0.984
C260	7	0.876	0.945

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:195000 | disease phenotypes: MIM:615774, MIM:617712

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
female infertility due to zona pellucida defect	Strong	Autosomal recessive	5

Mondo (2): female infertility due to zona pellucida defect (MONDO:0014342), oocyte maturation defect 3 (MONDO:0021574)

Orphanet (1): Female infertility due to zona pellucida defect (Orphanet:404466)

HPO phenotypes

4 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0008222	Female infertility
HP:0011462	Young adult onset
HP:6000328	Absent zona pellucida

GWAS associations

1 associations:

Study	Trait	p-value
GCST006296_2	Response to ziprazidone in schizophrenia	3e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067247 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	Kd	2.409	nM	CHEMBL3752910
8.62	ED50	2.409	nM	CHEMBL3752910
5.37	Kd	4247	nM	CHEMBL5653589
5.37	ED50	4247	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149818: Binding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0024	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149818: Binding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assay	kd	4.2473	uM

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	4
methyleugenol	increases expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
archazolid B	increases expression	1
Cadmium	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	increases methylation	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
CHEMBL5652860	Binding	Binding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ZP1 across ~30M SureChEMBL compounds — explore on Sugi Predict.