ZAN

Summary

ZAN (zonadhesin, HGNC:12857) is a protein-coding gene on chromosome 7q22.1, encoding Zonadhesin (Q9Y493). Binds in a species-specific manner to the zona pellucida of the egg.

This gene encodes a protein that functions in the species specificity of sperm adhesion to the egg zona pellucida. The encoded protein is located in the acrosome and may be involved in signaling or gamete recognition. An allelic polymorphism in this gene results in both functional and frameshifted alleles; the reference genome represents the functional allele. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 7455 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 427 total
• MANE Select transcript: NM_003386

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12857
Approved symbol	ZAN
Name	zonadhesin
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146839
Ensembl biotype	protein_coding
OMIM	602372
Entrez	7455

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000538115, ENST00000542585, ENST00000546213, ENST00000546292, ENST00000613979, ENST00000618565, ENST00000620596, ENST00000620868

RefSeq mRNA: 2 — MANE Select: NM_003386 NM_003386, NM_173059

CCDS: CCDS47663, CCDS47664

Canonical transcript exons

ENST00000613979 — 48 exons

Exon	Start	End
ENSE00002027059	100769880	100769974
ENSE00002032933	100768610	100768721
ENSE00002040570	100766525	100766666
ENSE00002045346	100767010	100767257
ENSE00002053630	100771844	100772020
ENSE00002054245	100767831	100768011
ENSE00002084623	100773285	100773493
ENSE00002284564	100773721	100773865
ENSE00003481255	100751182	100751266
ENSE00003484584	100790942	100791113
ENSE00003493909	100765352	100765554
ENSE00003502724	100789218	100789347
ENSE00003511055	100747550	100747641
ENSE00003523673	100738461	100738613
ENSE00003524942	100737262	100737349
ENSE00003530423	100797577	100797623
ENSE00003532317	100794120	100794258
ENSE00003538079	100791966	100792148
ENSE00003552286	100751712	100753229
ENSE00003555905	100760391	100760536
ENSE00003561647	100779446	100779750
ENSE00003567078	100748324	100748470
ENSE00003568170	100748137	100748215
ENSE00003576684	100763806	100763916
ENSE00003577297	100758202	100758343
ENSE00003584659	100735720	100735772
ENSE00003586258	100736483	100736629
ENSE00003586988	100762215	100762358
ENSE00003591974	100797366	100797465
ENSE00003601140	100759721	100759845
ENSE00003607531	100776440	100776564
ENSE00003608399	100795196	100795336
ENSE00003619692	100734027	100734221
ENSE00003620689	100775669	100775833
ENSE00003620906	100785997	100786141
ENSE00003630084	100758531	100758650
ENSE00003643940	100750625	100750896
ENSE00003645725	100764027	100764196
ENSE00003654447	100746538	100746702
ENSE00003660237	100784623	100784834
ENSE00003667362	100736809	100737080
ENSE00003673891	100787889	100788136
ENSE00003675048	100755226	100755410
ENSE00003680967	100775328	100775575
ENSE00003719913	100797707	100797797
ENSE00003729073	100793820	100794018
ENSE00003749920	100792405	100792479
ENSE00003892704	100733595	100733648

Expression profiles

Bgee: expression breadth tissue_specific, 7 present calls, max score 68.46.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0078 / max 9.0217, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
204545	0.0078	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	68.46	gold quality
endothelial cell	CL:0000115	64.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	62.98	gold quality
secondary oocyte	CL:0000655	62.18	gold quality
biceps brachii	UBERON:0001507	61.13	gold quality
amniotic fluid	UBERON:0000173	60.31	gold quality
esophagus squamous epithelium	UBERON:0006920	58.41	gold quality
cartilage tissue	UBERON:0002418	57.99	gold quality
tibia	UBERON:0000979	56.95	gold quality
trabecular bone tissue	UBERON:0002483	56.33	gold quality
vena cava	UBERON:0004087	56.22	gold quality
myocardium	UBERON:0002349	55.87	gold quality
tendon of biceps brachii	UBERON:0008188	55.63	gold quality
medial globus pallidus	UBERON:0002477	55.32	gold quality
layer of synovial tissue	UBERON:0007616	52.98	gold quality
bone marrow	UBERON:0002371	52.84	gold quality
skin of hip	UBERON:0001554	52.83	silver quality
cerebellar vermis	UBERON:0004720	52.58	gold quality
nasal cavity epithelium	UBERON:0005384	52.06	gold quality
sperm	CL:0000019	52.05	gold quality
globus pallidus	UBERON:0001875	52.05	gold quality
decidua	UBERON:0002450	51.79	gold quality
nipple	UBERON:0002030	51.75	gold quality
middle temporal gyrus	UBERON:0002771	51.28	gold quality
Brodmann (1909) area 46	UBERON:0006483	50.68	gold quality
vastus lateralis	UBERON:0001379	48.89	gold quality
quadriceps femoris	UBERON:0001377	48.69	gold quality
synovial joint	UBERON:0002217	48.61	gold quality
pylorus	UBERON:0001166	48.44	gold quality
oviduct epithelium	UBERON:0004804	48.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• VWD2, membrane/A5 antigen mu receptor, and mucin-like domains in zonadhesin are rapidly evolving and, thus, may be involved in binding to the ZP in a species-specific manner (PMID:17033959)
• Data identified three membrane-associated proteins, synaptosomal associated protein 25 (SNAP25), Thy-1 cell surface antigen and zonadhesin, interact with sex hormone binding globulin (SHBG)-ing proteins in the brain. (PMID:19724880)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zanl	ENSDARG00000056781
mus_musculus	Zan	ENSMUSG00000079173
rattus_norvegicus	Zan	ENSRNOG00000067638

Paralogs (19): CHRDL2 (ENSG00000054938), CHRD (ENSG00000090539), CHRDL1 (ENSG00000101938), TECTA (ENSG00000109927), VWF (ENSG00000110799), MUC5B (ENSG00000117983), KCP (ENSG00000135253), CRIM1 (ENSG00000150938), BMPER (ENSG00000164619), OTOGL (ENSG00000165899), VWCE (ENSG00000167992), VWC2L (ENSG00000174453), MUC6 (ENSG00000184956), OTOG (ENSG00000188162), VWC2 (ENSG00000188730), MUC2 (ENSG00000198788), MUC19 (ENSG00000205592), MUC5AC (ENSG00000215182), FCGBP (ENSG00000275395)

Protein

Protein identifiers

Zonadhesin — Q9Y493 (reviewed: Q9Y493)

All UniProt accessions (1): Q9Y493

UniProt curated annotations — full annotation on UniProt →

Function. Binds in a species-specific manner to the zona pellucida of the egg. May be involved in gamete recognition and/or signaling.

Subunit / interactions. Probably forms covalent oligomers.

Subcellular location. Cell membrane.

Tissue specificity. In testis, primarily in haploid spermatids.

Domain organisation. The MAM domains probably mediate sperm adhesion to the zona pellucida. During sperm migration through the reproductive tracts, the mucin-like domain might inhibit inappropriate trapping of spermatozoa or promoting adhesion to the oviductal isthmus. The VWFD domain 2 may mediate covalent oligomerization.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9Y493-1	3	yes
Q9Y493-2	1
Q9Y493-3	2
Q9Y493-4	4
Q9Y493-5	5
Q9Y493-6	6
Q9Y493-7	7

RefSeq proteins (2): NP_003377, NP_775082 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR000998	MAM_dom	Domain
IPR001007	VWF_dom	Domain
IPR001846	VWF_type-D	Domain
IPR002919	TIL_dom	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR014853	VWF/SSPO/ZAN-like_Cys-rich_dom	Domain
IPR025615	TILa_dom	Domain
IPR036084	Ser_inhib-like_sf	Homologous_superfamily
IPR050780	Mucin_vWF_Thrombospondin_sf	Family

Pfam: PF00094, PF00629, PF01826, PF08742, PF12714

UniProt features (97 total): sequence variant 23, domain 17, splice variant 12, glycosylation site 11, disulfide bond 10, compositionally biased region 9, region of interest 5, sequence conflict 5, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q9Y493 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (10): 1156–1291, 1178–1330, 1542–1680, 1564–1719, 1931–2069, 1953–2107, 2331–2468, 2712–2723, 2717–2732, 2734–2743

Glycosylation sites (11): 333, 493, 1112, 1188, 1685, 1804, 1900, 1946, 2203, 2542, 2701

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_CELL_CELL_ADHESION, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, GOBP_SPERM_EGG_RECOGNITION, MARTIN_VIRAL_GPCR_SIGNALING_UP, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GSE13522_CTRL_VS_T_CRUZI_Y_STRAIN_INF_SKIN_129_MOUSE_UP, GOCC_EXTERNAL_ENCAPSULATING_STRUCTURE, ZIM3_TARGET_GENES, GSE13229_MATURE_VS_INTMATURE_NKCELL_UP

GO Biological Process (3): binding of sperm to zona pellucida (GO:0007339), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155)

GO Molecular Function (2): extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sperm-egg recognition	1
cell adhesion	1
cellular process	1
structural molecule activity	1
extracellular matrix	1
binding	1
membrane	1
cell periphery	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZAN	TECTB	Q96PL2	922
ZAN	NID1	P14543	844
ZAN	ZP3	P21754	759
ZAN	SEMG2	Q02383	667
ZAN	SPESP1	Q6UW49	664
ZAN	MUC2	Q02817	645
ZAN	SPAM1	P38567	606
ZAN	ADAM2	P78326	594
ZAN	ZPBP	Q9BS86	589
ZAN	PKDREJ	Q9NTG1	567
ZAN	ACR	P10323	557
ZAN	SPACA1	Q9HBV2	524
ZAN	ZP2	Q05996	521
ZAN	CRISP1	P54107	514
ZAN	PRM2	P04554	511

IntAct

0 interactions, top by confidence:

BioGRID (2): ZAN (Affinity Capture-MS), ZAN (Affinity Capture-MS)

ESM2 similar proteins: A0A1F4, A6ZZG0, A7RJ13, A7SXG9, A8WVU7, A8X481, B1P1J2, B3A0Q2, B3A0S1, B3EWZ7, B3EX01, B3LQU0, D4AQH0, O46598, O88799, P03200, P09256, P10667, P14328, P15269, P22698, P28968, P38565, P68343, P68344, P97881, Q03178, Q07929, Q09419, Q09421, Q09550, Q09624, Q17802, Q21771, Q28983, Q54LH6, Q54LM2, Q5W9T8, Q66676, Q6FPN0

Diamond homologs: A0A2R4SV19, O88799, P57999, P85171, Q0PMG2, Q0WYX8, Q28983, Q3U492, Q6ZWJ8, Q8NFP4, Q9Y493, F1NBL0, P0DM55, P0DM56, P98167, Q6W4X9, Q700K0, Q8CG65, Q98UI9, P87498, Q8JZM4, Q8NFT8, Q91641, Q9IBG7, Q9Y6R7, A2AJA7, A2AJX4, B3EWZ5, B3EWZ6, B3EX02, O14786, P28824, P28827, P28828, P60755, P60756, P79795, P97333, P98073, Q16820

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	342
Likely benign	51
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

6669 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100735706:A:AG	acceptor_gain	1.0000
7:100736478:CCTA:C	acceptor_loss	1.0000
7:100736480:TA:T	acceptor_loss	1.0000
7:100736481:A:AC	acceptor_loss	1.0000
7:100736481:A:AG	acceptor_gain	1.0000
7:100736482:G:GG	acceptor_gain	1.0000
7:100736482:GAT:G	acceptor_gain	1.0000
7:100736627:G:GT	donor_gain	1.0000
7:100736628:AGGTG:A	donor_loss	1.0000
7:100736629:GGTGA:G	donor_loss	1.0000
7:100736630:G:GA	donor_loss	1.0000
7:100736631:T:G	donor_loss	1.0000
7:100737258:GCA:G	acceptor_loss	1.0000
7:100737259:CAGCT:C	acceptor_loss	1.0000
7:100737260:A:AG	acceptor_gain	1.0000
7:100737260:A:AT	acceptor_loss	1.0000
7:100737260:AGCT:A	acceptor_gain	1.0000
7:100737261:G:GA	acceptor_gain	1.0000
7:100737261:GC:G	acceptor_gain	1.0000
7:100737261:GCT:G	acceptor_gain	1.0000
7:100737261:GCTG:G	acceptor_gain	1.0000
7:100737347:GCG:G	donor_gain	1.0000
7:100737350:G:GG	donor_gain	1.0000
7:100738460:GTCT:G	acceptor_gain	1.0000
7:100748135:A:AG	acceptor_gain	1.0000
7:100748136:G:GG	acceptor_gain	1.0000
7:100748313:T:TA	acceptor_gain	1.0000
7:100748321:CA:C	acceptor_loss	1.0000
7:100748322:A:AG	acceptor_gain	1.0000
7:100748322:AGAG:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000075236 (7:100761243 G>A), RS1000133061 (7:100766610 G>A,T), RS1000135416 (7:100760081 G>A), RS1000172666 (7:100734486 G>T), RS1000265179 (7:100744144 C>G), RS1000266211 (7:100794803 C>T), RS1000293928 (7:100793754 G>A,T), RS1000317870 (7:100743855 C>A,T), RS1000326344 (7:100782973 A>G,T), RS1000416159 (7:100789084 C>A), RS1000425143 (7:100761426 G>A), RS1000455580 (7:100759991 A>G,T), RS1000475504 (7:100749393 C>T), RS1000490486 (7:100737425 G>A,C), RS1000500854 (7:100771200 A>G)

Disease associations

OMIM: gene MIM:602372 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006979_143	Heel bone mineral density	4.000000e-09
GCST008103_164	Bipolar disorder	7.000000e-06
GCST010002_259	Refractive error	3.000000e-16
GCST010101_9	White matter hyperintensities	2.000000e-08
GCST90002403_588	Red blood cell count	9.000000e-27
GCST90002403_589	Red blood cell count	1.000000e-16
GCST90020029_881	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005665	white matter hyperintensity measurement
EFO:0004305	erythrocyte count
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
quercitrin	increases expression	1
abrine	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases mutagenesis	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
p-Chloromercuribenzoic Acid	decreases expression	1

Clinical trials (associated diseases)

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