ZPBP

Summary

ZPBP (zona pellucida binding protein, HGNC:15662) is a protein-coding gene on chromosome 7p12.2, encoding Zona pellucida-binding protein 1 (Q9BS86). Plays a role in acrosome compaction and sperm morphogenesis.

ZPBP is one of several proteins that are thought to participate in secondary binding between acrosome-reacted sperm and the egg-specific extracellular matrix, the zona pellucida (McLeskey et al., 1998 [PubMed 9378618]).

Source: NCBI Gene 11055 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 66 (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 60 total — 1 pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_007009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15662
Approved symbol	ZPBP
Name	zona pellucida binding protein
Location	7p12.2
Locus type	gene with protein product
Status	Approved
Aliases	SP38, ZPBP1
Ensembl gene	ENSG00000042813
Ensembl biotype	protein_coding
OMIM	608498
Entrez	11055

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000046087, ENST00000413331, ENST00000419417, ENST00000450231, ENST00000465922, ENST00000491129, ENST00000903719, ENST00000903720

RefSeq mRNA: 2 — MANE Select: NM_007009 NM_001159878, NM_007009

CCDS: CCDS5509, CCDS55110

Canonical transcript exons

ENST00000046087 — 8 exons

Exon	Start	End
ENSE00000552558	50018240	50018316
ENSE00000683041	50031092	50031310
ENSE00000683043	50057989	50058141
ENSE00001136073	50093068	50093246
ENSE00001201739	49937441	49937622
ENSE00003593251	49983342	49983519
ENSE00003607850	50089629	50089709
ENSE00003788825	50081774	50081899

Expression profiles

Bgee: expression breadth ubiquitous, 103 present calls, max score 97.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4188 / max 344.6289, expressed in 25 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84096	0.3707	19
84097	0.0203	5
84094	0.0166	3
84095	0.0069	3
84093	0.0043	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adult organism	UBERON:0007023	97.84	gold quality
sperm	CL:0000019	97.65	gold quality
left testis	UBERON:0004533	97.51	gold quality
right testis	UBERON:0004534	97.29	gold quality
male germ cell	CL:0000015	97.28	gold quality
testis	UBERON:0000473	95.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.59	gold quality
buccal mucosa cell	CL:0002336	61.22	silver quality
islet of Langerhans	UBERON:0000006	58.49	gold quality
cerebellar hemisphere	UBERON:0002245	55.82	gold quality
cerebellar cortex	UBERON:0002129	55.77	gold quality
cranial nerve II	UBERON:0000941	55.72	silver quality
right hemisphere of cerebellum	UBERON:0014890	55.68	gold quality
cerebellum	UBERON:0002037	54.77	gold quality
tibialis anterior	UBERON:0001385	53.68	silver quality
skin of hip	UBERON:0001554	53.65	silver quality
cauda epididymis	UBERON:0004360	52.40	gold quality
pancreatic ductal cell	CL:0002079	52.08	silver quality
Brodmann (1909) area 46	UBERON:0006483	52.02	gold quality
quadriceps femoris	UBERON:0001377	51.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	51.57	gold quality
deltoid	UBERON:0001476	51.43	gold quality
right uterine tube	UBERON:0001302	51.06	gold quality
vastus lateralis	UBERON:0001379	50.81	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
thymus	UBERON:0002370	50.04	gold quality
caput epididymis	UBERON:0004358	50.04	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	313.01
E-GEOD-134144	yes	31.97
E-ANND-3	yes	4.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting ZPBP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-181A-2-3P	98.91	67.60	1168

Literature-anchored findings (GeneRIF, showing 2)

• Data show that loss of zona pellucida binding proteins 1 and 2 in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis. (PMID:17664285)
• Data suggest that missense mutations exert a dominant-negative effect due to altered ZPBP1 protein folding and protein:protein interactions in the acrosome. (PMID:21911476)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zpbp	ENSMUSG00000020193
rattus_norvegicus	Zpbp	ENSRNOG00000027801

Paralogs (1): ZPBP2 (ENSG00000186075)

Protein

Protein identifiers

Zona pellucida-binding protein 1 — Q9BS86 (reviewed: Q9BS86)

Alternative names: Inner acrosomal membrane IAM38, Sp38

All UniProt accessions (3): C9JIS7, Q9BS86, F8WDW2

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in acrosome compaction and sperm morphogenesis. Is implicated in sperm-oocyte interaction during fertilization.

Subunit / interactions. Interacts with CFAP65.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Acrosome membrane. Secreted.

Tissue specificity. Expressed specifically in testis.

Post-translational modifications. N-glycosylated.

Disease relevance. Spermatogenic failure 66 (SPGF66) [MIM:619799] An autosomal recessive male infertility disorder characterized by globozoospermia. Affected individuals have a normal sperm count, but spermatozoa are round-headed and lack the acrosome. In addition to pure globozoospermia, some patients have a mixture of acrosomeless spermatozoa and spermatozoa with small or detached acrosomes, which is defined as acrosomal hypoplasia. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the zona pellucida-binding protein Sp38 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BS86-1	1	yes
Q9BS86-2	2

RefSeq proteins (2): NP_001153350, NP_008940* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007110	Ig-like_dom	Domain
IPR010857	Sp38-bd	Family
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR048805	ZPBP1/2_C	Domain
IPR048806	ZPBP1/2_N	Domain

Pfam: PF07354, PF20626

UniProt features (15 total): sequence variant 8, glycosylation site 3, signal peptide 1, chain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BS86-F1	82.47	0.66

Functional residue map

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

Glycosylation sites (3): 114, 187, 340

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 100 (showing top): GOBP_SINGLE_FERTILIZATION, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, GOBP_SECRETORY_GRANULE_ORGANIZATION, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_SPERM_EGG_RECOGNITION, GOBP_ACROSOME_ASSEMBLY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GNF2_CCNA1, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_FERTILIZATION

GO Biological Process (2): acrosome assembly (GO:0001675), binding of sperm to zona pellucida (GO:0007339)

GO Molecular Function (0):

GO Cellular Component (7): acrosomal vesicle (GO:0001669), acrosomal membrane (GO:0002080), zona pellucida receptor complex (GO:0002199), extracellular region (GO:0005576), nucleus (GO:0005634), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
developmental process involved in reproduction	1
spermatid development	1
cellular component assembly involved in morphogenesis	1
cellular process involved in reproduction in multicellular organism	1
secretory granule organization	1
organelle assembly	1
sperm-egg recognition	1
secretory granule	1
acrosomal vesicle	1
secretory granule membrane	1
chaperonin-containing T-complex	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZPBP	SPA17	Q15506	863
ZPBP	SPACA1	Q9HBV2	828
ZPBP	DPY19L2	Q6NUT2	818
ZPBP	SPATA16	Q9BXB7	789
ZPBP	ABHD2	P08910	689
ZPBP	SPESP1	Q6UW49	681
ZPBP	GRB7	Q14451	670
ZPBP	ACRBP	Q8NEB7	649
ZPBP	SPACDR	Q8IZ16	647
ZPBP	IKZF3	Q9UKT9	643
ZPBP	GRB10	Q13322	615
ZPBP	ZAN	Q9Y493	589
ZPBP	IKZF1	Q13422	578
ZPBP	SPACA3	Q8IXA5	560
ZPBP	ROPN1	Q9HAT0	550

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ZPBP	CALU	psi-mi:“MI:0915”(physical association)	0.370
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): ZPBP (Two-hybrid), ZPBP (Proximity Label-MS), ZPBP (Affinity Capture-MS), ZPBP (Two-hybrid)

ESM2 similar proteins: A0JNQ6, A2RT67, A2RUS2, A6NC42, A6NGQ2, A9X185, O75031, O75817, O94955, O95267, P50747, Q06VW1, Q0II25, Q0ZFW8, Q1RMS8, Q1RMZ1, Q29108, Q2TBA3, Q3T0J1, Q3TYS2, Q4VX76, Q568D5, Q568M3, Q587J7, Q5JSQ8, Q5T9G4, Q5ZLS2, Q62522, Q69ZK0, Q6AYA6, Q6P5G6, Q7Z7H3, Q80X86, Q86WV5, Q8BXK4, Q8C0Q9, Q8CHQ0, Q8TCU6, Q8WUE5, Q91Z62

Diamond homologs: Q29108, Q62522, Q6PVW7, Q6Q2W4, Q6X782, Q6X784, Q6X786, Q9BS86

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	35
Likely benign	14
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1344566	NM_007009.3(ZPBP):c.931C>T (p.Gln311Ter)	Pathogenic

SpliceAI

2539 predictions. Top by Δscore:

Variant	Effect	Δscore
7:49937621:CA:C	acceptor_gain	1.0000
7:49937623:C:CC	acceptor_gain	1.0000
7:49983341:CCA:C	donor_gain	1.0000
7:50031307:TAAG:T	acceptor_gain	1.0000
7:50031311:C:CC	acceptor_gain	1.0000
7:50058142:C:CC	acceptor_gain	1.0000
7:50080141:C:CT	donor_gain	1.0000
7:50080142:T:TT	donor_gain	1.0000
7:50089710:C:CC	acceptor_gain	1.0000
7:50104407:GTACA:G	donor_gain	1.0000
7:50104412:G:GG	donor_gain	1.0000
7:49912123:G:GT	donor_gain	0.9900
7:49937620:TCA:T	acceptor_gain	0.9900
7:49937621:CAC:C	acceptor_gain	0.9900
7:49937622:AC:A	acceptor_loss	0.9900
7:49937624:T:G	acceptor_loss	0.9900
7:49952878:AG:A	donor_gain	0.9900
7:49983338:ATAC:A	donor_loss	0.9900
7:49983339:T:TG	donor_loss	0.9900
7:49983340:A:AC	donor_gain	0.9900
7:49983340:ACCAC:A	donor_loss	0.9900
7:49983341:C:CC	donor_gain	0.9900
7:49983341:C:CT	donor_gain	0.9900
7:49983484:T:C	acceptor_gain	0.9900
7:50030359:A:C	donor_gain	0.9900
7:50031085:GACTT:G	donor_loss	0.9900
7:50031086:ACTTA:A	donor_loss	0.9900
7:50031087:CTT:C	donor_loss	0.9900
7:50031088:TTACC:T	donor_loss	0.9900
7:50031089:T:TA	donor_loss	0.9900

AlphaMissense

2264 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:50081802:C:A	W102C	0.998
7:50081802:C:G	W102C	0.998
7:50081804:A:G	W102R	0.997
7:50081804:A:T	W102R	0.997
7:50058056:A:C	C140W	0.995
7:50081854:C:G	C85S	0.995
7:50081855:A:G	C85R	0.995
7:50081855:A:T	C85S	0.995
7:49983398:C:G	C302S	0.994
7:49983399:A:T	C302S	0.994
7:50058058:A:G	C140R	0.994
7:50058071:A:C	S135R	0.994
7:50058071:A:T	S135R	0.994
7:50058073:T:G	S135R	0.994
7:49983399:A:G	C302R	0.993
7:50081854:C:T	C85Y	0.993
7:50081868:A:C	S80R	0.993
7:50081868:A:T	S80R	0.993
7:50081870:T:G	S80R	0.993
7:49937616:C:G	C323S	0.992
7:49937616:C:T	C323Y	0.992
7:49937617:A:T	C323S	0.992
7:49983397:G:C	C302W	0.992
7:50031269:A:C	Y177D	0.992
7:50058057:C:G	C140S	0.992
7:50058057:C:T	C140Y	0.992
7:50058058:A:T	C140S	0.992
7:50081853:A:C	C85W	0.992
7:49937615:G:C	C323W	0.991
7:49937617:A:G	C323R	0.991

dbSNP variants (sampled 300 via entrez): RS1000000584 (7:50094801 T>C), RS1000012260 (7:49949496 A>C), RS1000018716 (7:49882754 T>C), RS1000023447 (7:49929704 G>A), RS1000028091 (7:49996821 C>T), RS1000057468 (7:49903993 A>G), RS1000062416 (7:49841043 A>C), RS1000089037 (7:49967973 C>A,G,T), RS1000091225 (7:49973763 G>A), RS1000125961 (7:50059090 T>C), RS1000142679 (7:49897190 C>T), RS1000146899 (7:49917721 T>C,G), RS1000152848 (7:50059167 T>C), RS1000157808 (7:50015389 T>C), RS1000186590 (7:49869752 C>A)

Disease associations

OMIM: gene MIM:608498 | disease phenotypes: MIM:619799

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 66	Limited	Unknown

Mondo (1): spermatogenic failure 66 (MONDO:0030716)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0012205	Globozoospermia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000879_33	Crohn’s disease	1.000000e-08
GCST000892_4	Total ventricular volume (Alzheimer’s disease interaction)	9.000000e-06
GCST001725_93	Inflammatory bowel disease	7.000000e-15
GCST004131_94	Inflammatory bowel disease	5.000000e-11
GCST004132_57	Crohn’s disease	9.000000e-12
GCST005950_9	Body mass index x sex x age interaction (4df test)	2.000000e-09
GCST005951_200	Body mass index	2.000000e-08
GCST005951_57	Body mass index	3.000000e-10
GCST005953_3	Body mass index (age <50)	8.000000e-10
GCST009391_1696	Metabolite levels	5.000000e-06
GCST90002382_370	Eosinophil percentage of white cells	4.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010344	cholesteryl ester 18:1 measurement
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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