ZPLD1

Summary

ZPLD1 (zona pellucida like domain containing 1, HGNC:27022) is a protein-coding gene on chromosome 3q12.3, encoding Zona pellucida-like domain-containing protein 1 (Q8TCW7). Glycoprotein which is a component of the gelatinous extracellular matrix in the cupulae of the vestibular organ.

Predicted to act upstream of or within vestibular reflex. Predicted to be located in cytoplasmic vesicle membrane and extracellular region. Predicted to be active in cell surface and extracellular space.

Source: NCBI Gene 131368 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 74 total
• MANE Select transcript: NM_001329788

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27022
Approved symbol	ZPLD1
Name	zona pellucida like domain containing 1
Location	3q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170044
Ensembl biotype	protein_coding
OMIM	615915
Entrez	131368

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000306176, ENST00000466937, ENST00000478083, ENST00000491959

RefSeq mRNA: 2 — MANE Select: NM_001329788 NM_001329788, NM_175056

CCDS: CCDS2947, CCDS87115

Canonical transcript exons

ENST00000466937 — 12 exons

Exon	Start	End
ENSE00001072972	102477012	102477041
ENSE00001072973	102470394	102470502
ENSE00001072974	102457781	102457853
ENSE00001072975	102456193	102456374
ENSE00001072976	102462281	102462378
ENSE00001072978	102468964	102469135
ENSE00001072980	102452919	102453139
ENSE00001161810	102477443	102479841
ENSE00001209460	102464171	102464251
ENSE00001824084	102435015	102435154
ENSE00001924477	102436860	102436973
ENSE00003674609	102438480	102438593

Expression profiles

Bgee: expression breadth broad, 71 present calls, max score 82.97.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	82.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.81	silver quality
islet of Langerhans	UBERON:0000006	75.41	gold quality
oocyte	CL:0000023	72.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.32	gold quality
gall bladder	UBERON:0002110	68.65	gold quality
decidua	UBERON:0002450	55.66	gold quality
metanephros cortex	UBERON:0010533	51.45	gold quality
stromal cell of endometrium	CL:0002255	51.33	gold quality
duodenum	UBERON:0002114	50.26	gold quality
buccal mucosa cell	CL:0002336	50.01	gold quality
pancreas	UBERON:0001264	48.55	gold quality
metanephros	UBERON:0000081	48.11	gold quality
adult mammalian kidney	UBERON:0000082	46.20	gold quality
colonic epithelium	UBERON:0000397	46.12	gold quality
sural nerve	UBERON:0015488	45.19	gold quality
endometrium	UBERON:0001295	44.49	gold quality
kidney	UBERON:0002113	44.39	gold quality
cortex of kidney	UBERON:0001225	43.58	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
oviduct epithelium	UBERON:0004804	43.29	silver quality
placenta	UBERON:0001987	42.68	silver quality
monocyte	CL:0000576	42.65	silver quality
sperm	CL:0000019	42.16	silver quality
lower lobe of lung	UBERON:0008949	42.10	silver quality
leukocyte	CL:0000738	41.92	silver quality
hindlimb stylopod muscle	UBERON:0004252	41.90	gold quality
smooth muscle tissue	UBERON:0001135	41.82	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting ZPLD1, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836

Literature-anchored findings (GeneRIF, showing 2)

• this protein may be part of the complex signaling pathway implicated in cerebral cavernous malformation formation (PMID:18632209)
• associations revealed between genetic polymorphisms located in the flanking region of the ARID1B genes and hypoesthesia (PMID:23834954)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zpld1a	ENSDARG00000061835
danio_rerio	zpld1b	ENSDARG00000063372
mus_musculus	Zpld1	ENSMUSG00000064310
rattus_norvegicus	Zpld1	ENSRNOG00000039517

Paralogs (5): TECTB (ENSG00000119913), OIT3 (ENSG00000138315), UMOD (ENSG00000169344), GP2 (ENSG00000169347), UMODL1 (ENSG00000177398)

Protein

Protein identifiers

Zona pellucida-like domain-containing protein 1 — Q8TCW7 (reviewed: Q8TCW7)

Alternative names: Cupulin

All UniProt accessions (1): Q8TCW7

UniProt curated annotations — full annotation on UniProt →

Function. Glycoprotein which is a component of the gelatinous extracellular matrix in the cupulae of the vestibular organ.

Subcellular location. Cytoplasmic vesicle membrane Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Detected in placenta, kidney, lung, pancreas and at very low level in other tissues.

Post-translational modifications. Proteolytically cleaved before the transmembrane segment to yield the secreted form found in the extracellular matrix of the cupula.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TCW7-1	1	yes
Q8TCW7-2	2

RefSeq proteins (2): NP_001316717, NP_778226 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001507	ZP_dom	Domain
IPR042235	ZP-C_dom	Homologous_superfamily
IPR055355	ZP-C	Domain
IPR055356	ZP-N	Domain

Pfam: PF00100, PF23344

UniProt features (22 total): disulfide bond 4, sequence variant 3, chain 2, glycosylation site 2, topological domain 2, compositionally biased region 2, signal peptide 1, site 1, splice variant 1, sequence conflict 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCW7-F1	77.56	0.38

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 (1): 319–320 (cleavage)

Disulfide bonds (4): 44–155, 79–104, 235–296, 255–313

Glycosylation sites (2): 121, 164

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 49 (showing top): GOZGIT_ESR1_TARGETS_DN, GOCC_CELL_SURFACE, GOBP_REFLEX, POU3F2_02, chr3q12, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_WITH_LMP1_UP, TEF_Q6, VDR_Q6, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, NABA_ECM_GLYCOPROTEINS, ZNF274_TARGET_GENES, MIR3662, MIR548AR_3P, MIR548F_3P, MIR548BC

GO Biological Process (1): vestibular reflex (GO:0060005)

GO Molecular Function (0):

GO Cellular Component (6): obsolete extracellular space (GO:0005615), cell surface (GO:0009986), cytoplasmic vesicle membrane (GO:0030659), extracellular region (GO:0005576), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
reflex	1
vesicle membrane	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

578 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZPLD1	BRICD5	Q6PL45	566
ZPLD1	FNDC7	Q5VTL7	523
ZPLD1	C10orf120	Q5SQS8	520
ZPLD1	CUZD1	Q86UP6	518
ZPLD1	FAM162B	Q5T6X4	495
ZPLD1	AKR1E2	Q96JD6	491
ZPLD1	TRIM42	Q8IWZ5	487
ZPLD1	C5orf47	Q569G3	483
ZPLD1	GALNTL6	Q49A17	472
ZPLD1	CIB3	Q96Q77	461
ZPLD1	HS6ST3	Q8IZP7	456
ZPLD1	OTOG	Q6ZRI0	446
ZPLD1	AGR3	Q8TD06	435
ZPLD1	CCDC27	Q2M243	433
ZPLD1	CLEC19A	Q6UXS0	431

IntAct

3 interactions, top by confidence:

A	B	Type	Score
RARG	RARA	psi-mi:“MI:0914”(association)	0.530
ZPLD1	CEACAM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): CEACAM8 (Affinity Capture-MS), ZPLD1 (Affinity Capture-MS), GNPTAB (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), RTN4 (Affinity Capture-MS), TMX1 (Affinity Capture-MS), SDF2L1 (Affinity Capture-MS), STEAP2 (Affinity Capture-MS), GNPTG (Affinity Capture-MS), FAM207A (Affinity Capture-MS), STEAP2 (Affinity Capture-MS), RTN4 (Affinity Capture-MS), TMX1 (Affinity Capture-MS), LRRC16A (Affinity Capture-MS), CEACAM8 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, A7E2Z9, A8MWY0, A8WCC4, C0H9B6, C6KFA3, F1QR43, F1R520, O13097, O18756, O73874, O94923, O94985, P07224, P07225, P0C152, P13612, P19218, P24387, P24668, P26009, P53813, P98118, Q00651, Q08761, Q0VCT4, Q13822, Q16819, Q28CF8, Q3UZV7, Q5HYA8, Q64610, Q66IR0, Q6AY20, Q6BEA0, Q6F3F9, Q6Q0N0, Q86SQ4, Q8BGZ8, Q8TCW7

Diamond homologs: C0H9B6, P54097, Q66IR0, Q862Z3, Q8BGZ8, Q8TCW7, Q95JJ6, A2ARV4, B3EWY9, B5DFC9, C0HL13, G3V928, O08523, O35568, O42182, O57382, O64758, O73775, O75095, O75443, O88322, P06579, P07225, P07911, P14543, P15306, P19218, P23142, P25291, P27590, P35444, P35445, P35555, P35556, P35951, P48733, P48960, P49747, P53813, P55259

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5138 predictions. Top by Δscore:

Variant	Effect	Δscore
3:102324863:GTTCT:G	donor_gain	1.0000
3:102324868:G:GG	donor_gain	1.0000
3:102377682:G:GT	donor_gain	1.0000
3:102438593:GGTA:G	donor_loss	1.0000
3:102438594:G:GC	donor_loss	1.0000
3:102438594:G:GG	donor_gain	1.0000
3:102438595:T:G	donor_loss	1.0000
3:102438598:GT:G	donor_gain	1.0000
3:102452917:A:AG	acceptor_gain	1.0000
3:102452918:G:GG	acceptor_gain	1.0000
3:102453137:GTG:G	donor_gain	1.0000
3:102453137:GTGGT:G	donor_loss	1.0000
3:102453138:TGGTA:T	donor_loss	1.0000
3:102453139:GGT:G	donor_loss	1.0000
3:102453140:G:C	donor_loss	1.0000
3:102456375:G:GG	donor_gain	1.0000
3:102457852:AC:A	donor_gain	1.0000
3:102457854:G:GG	donor_gain	1.0000
3:102468947:C:G	acceptor_gain	1.0000
3:102468955:A:AG	acceptor_gain	1.0000
3:102468956:A:G	acceptor_gain	1.0000
3:102468957:A:G	acceptor_gain	1.0000
3:102468960:TTA:T	acceptor_loss	1.0000
3:102468961:TAG:T	acceptor_loss	1.0000
3:102468962:A:AG	acceptor_gain	1.0000
3:102468962:AG:A	acceptor_loss	1.0000
3:102468963:G:GG	acceptor_gain	1.0000
3:102469132:GCCG:G	donor_gain	1.0000
3:102469133:CCGGT:C	donor_loss	1.0000
3:102469134:CGG:C	donor_loss	1.0000

AlphaMissense

2720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:102452979:G:A	C56Y	1.000
3:102456328:T:C	C155R	1.000
3:102456329:G:A	C155Y	1.000
3:102456330:T:G	C155W	1.000
3:102464193:T:A	C235S	1.000
3:102464193:T:C	C235R	1.000
3:102464194:G:A	C235Y	1.000
3:102464194:G:C	C235S	1.000
3:102464195:C:G	C235W	1.000
3:102469023:T:C	F274S	1.000
3:102469043:T:C	F281L	1.000
3:102469044:T:G	F281C	1.000
3:102469045:T:A	F281L	1.000
3:102469045:T:G	F281L	1.000
3:102469088:T:A	C296S	1.000
3:102469088:T:C	C296R	1.000
3:102469089:G:A	C296Y	1.000
3:102469089:G:C	C296S	1.000
3:102469090:C:G	C296W	1.000
3:102438563:T:A	C26S	0.999
3:102438564:G:C	C26S	0.999
3:102452942:T:A	C44S	0.999
3:102452942:T:C	C44R	0.999
3:102452943:G:A	C44Y	0.999
3:102452943:G:C	C44S	0.999
3:102452943:G:T	C44F	0.999
3:102452944:T:G	C44W	0.999
3:102452978:T:A	C56S	0.999
3:102452978:T:C	C56R	0.999
3:102452979:G:C	C56S	0.999

dbSNP variants (sampled 300 via entrez): RS1000023602 (3:102445523 T>A,G), RS1000023668 (3:102408865 A>C), RS1000060112 (3:102395722 C>G,T), RS1000075740 (3:102388455 C>G), RS1000081226 (3:102446619 AG>A), RS1000138127 (3:102408615 T>C), RS1000155441 (3:102472120 A>G), RS1000168930 (3:102386593 T>A,C), RS1000238877 (3:102466610 G>A,T), RS1000254171 (3:102428540 T>C), RS1000262843 (3:102473357 C>A), RS1000278328 (3:102434087 A>G), RS1000281553 (3:102386332 C>A,G,T), RS1000282585 (3:102408784 T>C,G), RS1000313324 (3:102427015 T>C)

Disease associations

OMIM: gene MIM:615915 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001033_15	Type 2 diabetes	3.000000e-06
GCST002090_5	Sensory disturbances after bilateral sagittal split ramus osteotomy	2.000000e-06
GCST002938_10	Copper levels	9.000000e-07
GCST003264_858	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST004579_3	Waist-to-hip circumference ratio (alcohol intake interaction)	2.000000e-06
GCST006277_3	Response to ranibizumab in age-related macular degeneration (exudative)	2.000000e-06
GCST007121_3	Multiple sclerosis and C-reactive protein levels (pleiotropy)	1.000000e-08
GCST007122_2	Multiple sclerosis and triglyceride levels (pleiotropy)	1.000000e-08
GCST010396_155	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-06
GCST012292_4	Schizophrenia, bipolar disorder or recurrent major depressive disorder x sex interaction	1.000000e-06
GCST012295_5	Schizophrenia, bipolar disorder or recurrent major depressive disorder x sex interaction	2.000000e-06
GCST012298_5	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	4.000000e-07
GCST012299_9	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction (3df)	5.000000e-06
GCST012301_15	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	5.000000e-07

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005324	post-operative sensory disturbance
EFO:0004713	FEV/FVC ratio
EFO:0004343	waist-hip ratio
EFO:0008348	response to ranibizumab
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0007874	gut microbiome measurement
EFO:0004952	disease recurrence
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	6
trichostatin A	decreases expression	2
Aflatoxin B1	decreases methylation	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Medroxyprogesterone Acetate	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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