TJP2

Summary

TJP2 (tight junction protein 2, HGNC:11828) is a protein-coding gene on chromosome 9q21.11, encoding Tight junction protein 2 (Q9UDY2). Plays a role in tight junctions and adherens junctions.

This gene encodes a zonula occluden that is a member of the membrane-associated guanylate kinase homolog family. The encoded protein functions as a component of the tight junction barrier in epithelial and endothelial cells and is necessary for proper assembly of tight junctions. Mutations in this gene have been identified in patients with hypercholanemia, and genomic duplication of a 270 kb region including this gene causes autosomal dominant deafness-51. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 9414 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cholestasis, progressive familial intrahepatic, 4 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 912 total — 55 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 16
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_004817

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11828
Approved symbol	TJP2
Name	tight junction protein 2
Location	9q21.11
Locus type	gene with protein product
Status	Approved
Aliases	ZO-2, X104, ZO2
Ensembl gene	ENSG00000119139
Ensembl biotype	protein_coding
OMIM	607709
Entrez	9414

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 22 protein_coding, 9 retained_intron, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000348208, ENST00000377245, ENST00000377259, ENST00000413932, ENST00000423935, ENST00000498204, ENST00000535702, ENST00000539225, ENST00000606364, ENST00000636247, ENST00000636438, ENST00000643713, ENST00000647986, ENST00000648042, ENST00000648087, ENST00000648153, ENST00000648402, ENST00000648460, ENST00000648862, ENST00000649114, ENST00000649134, ENST00000649783, ENST00000649927, ENST00000649939, ENST00000649943, ENST00000650084, ENST00000650333, ENST00000650353, ENST00000650378, ENST00000650460, ENST00000650522, ENST00000896723, ENST00000896724, ENST00000896725, ENST00000965864, ENST00000965865

RefSeq mRNA: 11 — MANE Select: NM_004817 NM_001170414, NM_001170415, NM_001170416, NM_001369870, NM_001369871, NM_001369872, NM_001369873, NM_001369874, NM_001369875, NM_004817, NM_201629

CCDS: CCDS55315, CCDS55316, CCDS6627, CCDS6628, CCDS94416

Canonical transcript exons

ENST00000377245 — 23 exons

Exon	Start	End
ENSE00000705638	69249375	69249485
ENSE00000803640	69248012	69248224
ENSE00001229349	69251035	69251364
ENSE00001229501	69252815	69252900
ENSE00001473273	69174277	69174432
ENSE00002279487	69254209	69255208
ENSE00003791996	69225304	69225407
ENSE00003792043	69239937	69240147
ENSE00003793386	69236028	69236238
ENSE00003793747	69226022	69226175
ENSE00003794085	69230082	69230232
ENSE00003794825	69237878	69237973
ENSE00003794846	69212548	69212601
ENSE00003795694	69236949	69237136
ENSE00003795858	69227765	69227873
ENSE00003795984	69229184	69229250
ENSE00003796302	69234439	69234547
ENSE00003796351	69238710	69238789
ENSE00003797510	69220887	69221496
ENSE00003798658	69227981	69228114
ENSE00003800179	69218257	69218359
ENSE00003800356	69216339	69216463
ENSE00003800399	69246690	69246790

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1706 / max 331.1897, expressed in 1769 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96829	15.2861	1622
96821	4.1910	1034
96819	3.1799	916
96822	1.6214	692
96836	0.7619	91
96817	0.2987	159
96818	0.2739	155
96816	0.2434	137
96812	0.2092	59
96820	0.2081	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.16	gold quality
descending thoracic aorta	UBERON:0002345	97.11	gold quality
thoracic aorta	UBERON:0001515	96.56	gold quality
ascending aorta	UBERON:0001496	96.54	gold quality
right coronary artery	UBERON:0001625	96.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.44	gold quality
right lung	UBERON:0002167	96.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.18	gold quality
duodenum	UBERON:0002114	96.04	gold quality
right lobe of liver	UBERON:0001114	96.00	gold quality
right lobe of thyroid gland	UBERON:0001119	95.99	gold quality
lower esophagus mucosa	UBERON:0035834	95.96	gold quality
esophagus mucosa	UBERON:0002469	95.93	gold quality
thyroid gland	UBERON:0002046	95.85	gold quality
liver	UBERON:0002107	95.84	gold quality
upper lobe of left lung	UBERON:0008952	95.84	gold quality
lung	UBERON:0002048	95.83	gold quality
left lobe of thyroid gland	UBERON:0001120	95.76	gold quality
adipose tissue	UBERON:0001013	95.61	gold quality
body of stomach	UBERON:0001161	95.58	gold quality
esophagus	UBERON:0001043	95.53	gold quality
stomach	UBERON:0000945	95.42	gold quality
left coronary artery	UBERON:0001626	95.29	gold quality
tibial nerve	UBERON:0001323	95.28	gold quality
fundus of stomach	UBERON:0001160	95.22	gold quality
lower esophagus	UBERON:0013473	95.18	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.17	gold quality
right ovary	UBERON:0002118	94.98	gold quality
omental fat pad	UBERON:0010414	94.95	gold quality
urinary bladder	UBERON:0001255	94.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.70
E-ENAD-27	no	3.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

53 targeting TJP2, 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-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-106A-3P	99.53	67.58	995

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• Familial hypercholanemia in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). (PMID:12704386)
• Sertoli cells associated with carcinoma in situ of the testicles show an altered distribution of ZO-2 and loss of blood-testis barrier function. (PMID:17217619)
• TJP2 did not reveal a otosclerosis-causing mutation (PMID:18224337)
• upregulation of ZO-2 by Angiopoietin-1 which reduces vascular endothelial growth factor-induced brain endothelial permeability (PMID:19148554)
• Structural comparison shows that the ZO-2 PDZ2 homodimer may have a similar ligand-binding pattern to the ZO-1 PDZ2-connexin 43 complex. (PMID:19342771)
• The tight junction protein ZO-2 is involved in regulation of vascular smooth muscle cells growth control upon vascular injury that is mediated by the transcription factor Stat1. (PMID:19380416)
• ZO-2 may serve to anchor regulatory proteins at gap junctions composed of Cx36. (PMID:19418635)
• Study shows that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus. (PMID:19784548)
• TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population. (PMID:20602916)
• the first PDZ domain of zona occludens-1 (ZO-1) and 2 (ZO-2) interacts with the carboxy-terminal PDZ binding motif of TAZ (PMID:20850437)
• ZO-2 interacts with YAP2 to form complex; ZO-2 facilitates both nuclear translocation of YAP2 & pro-apoptotic function of YAP2; YAP2/ZO-2 complex appears to be involved in cell detachment (PMID:20868367)
• The identification of ZASP helps to unfold the complex nuclear molecular arrays that form on ZO-2 scaffolds. (PMID:20868680)
• these findings imply involvement of the ZO-2 tight junction independent signaling complex containing Jak1 and uPAR in VSMC intercellular communications. (PMID:21679692)
• AmotL1 and ZO-2 are two candidates that could be harnessed to control the oncogenic function of YAP. (PMID:21685940)
• ZO-2 inhibits the Wnt signaling pathway, reduces cell proliferation, and promotes apoptosis; its absence, mutation, or overexpression is present in various human diseases, including deafness and cancer. (PMID:22671599)
• demonstrated that ZO-2 inhibition increases invasive and migrative capacities of invasive tumor cells. This was associated with an increase of MT1-MMP (PMID:23605953)
• the Alu-related transcript of TJP2 gene (TJP2-Alu transcript) was differentially expressed between colorectal tumor and normal tissues; potential diagnostic markers for colorectal cancer. (PMID:23612256)
• JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton. (PMID:23885123)
• Protein-truncating mutations in the tight junction protein 2 gene cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. (PMID:24614073)
• Claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO2. (PMID:25712527)
• TJP2 deficiency may predispose to hepatocellular carcinoma in early childhood (PMID:25921221)
• Data identified two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment. (PMID:26668150)
• A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39 (PMID:28039895)
• Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23-2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51-37.26%). (PMID:28073941)
• Studies indicate the modular and supramodular organization of zonula occludens protein 2 (ZO-2) that allows it to interact with a wide variety of molecules, including cell-cell adhesion proteins, cytoskeletal components, and nuclear factors. (PMID:28415133)
• Biochemistry and microscopy approaches in T cells confirmed SNX27/ZO-2 PDZ-dependent interaction, and demonstrated its role controlling the dynamic localization of ZO-2 at the IS (PMID:28477369)
• Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. (PMID:29238877)
• Results suggested that a reduction in CLDN18-dependent ZO-2 expression enhances MMP2 expression in lung adenocarcinoma cells, resulting in the promotion of the cell migration. (PMID:30713254)
• It is a potential target of miR-543. (PMID:31428943)
• Supra-molecular assembly and positioning of tight junctions as continuous networks of adhesion strands are dependent on the membrane-associated scaffolding proteins ZO1 and ZO2. (PMID:31675499)
• TJP2 hepatobiliary disorders: Novel variants and clinical diversity. (PMID:31696999)
• New tight junction protein 2 variant causing progressive familial intrahepatic cholestasis type 4 in adults: A case report. (PMID:32089630)
• Tight junction protein ZO-2 modulates the nuclear accumulation of transcription factor TEAD. (PMID:34010016)
• p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP. (PMID:37995182)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tjp2b	ENSDARG00000023443
danio_rerio	tjp2a	ENSDARG00000063309
mus_musculus	Tjp2	ENSMUSG00000024812
rattus_norvegicus	Tjp2	ENSRNOG00000015030
drosophila_melanogaster	pyd	FBGN0262614
caenorhabditis_elegans	zoo-1	WBGENE00013683

Paralogs (3): TJP1 (ENSG00000104067), TJP3 (ENSG00000105289), DLG5 (ENSG00000151208)

Protein

Protein identifiers

Tight junction protein 2 — Q9UDY2 (reviewed: Q9UDY2)

Alternative names: Tight junction protein ZO-2, Zona occludens protein 2, Zonula occludens protein 2

All UniProt accessions (13): A0A1B0GTW1, A0A3B3IRI3, A0A3B3IRV6, Q9UDY2, A0A3B3IS03, A0A3B3ISF1, A0A3B3ISZ5, A0A3B3IT83, A0A3B3ITE1, A0A3B3IU26, A0A3B3IU51, B1AN86, U3KQJ2

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in tight junctions and adherens junctions. Acts as a positive regulator of RANKL-induced osteoclast differentiation, potentially via mediating downstream transcriptional activity.

Subunit / interactions. Homodimer. Interacts (via PDZ2 domain) with TJP1/ZO1 (via PDZ2 domain). Interacts with OCLN. Interacts with UBN1. Interacts with SAFB in the nucleus. Interacts with SCRIB. Interacts with USP53 (via the C-terminal region). Interacts with claudins, including CLDN1, CLDN2, CLDN3, CLDN5 and CLDN7. Interacts with CLDN18. Interacts (via N-terminus) with CTNNA1.

Subcellular location. Cell junction. Adherens junction. Cell membrane. Tight junction. Nucleus.

Tissue specificity. This protein is found in epithelial cell junctions. Isoform A1 is abundant in the heart and brain. Detected in brain and skeletal muscle. It is present almost exclusively in normal tissues. Isoform C1 is expressed at high level in the kidney, pancreas, heart and placenta. Not detected in brain and skeletal muscle. Found in normal as well as in most neoplastic tissues.

Disease relevance. Hypercholanemia, familial, 1 (FHCA1) [MIM:607748] A disorder characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. Cholestasis, progressive familial intrahepatic, 4 (PFIC4) [MIM:615878] A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. PFIC4 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative splicing of isoform A1. Produced by alternative splicing of isoform A1. Produced by alternative promoter usage. Produced by alternative splicing of isoform C1.

Similarity. Belongs to the MAGUK family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9UDY2-1	A1	yes
Q9UDY2-2	A2
Q9UDY2-5	A3
Q9UDY2-3	C1
Q9UDY2-4	C2
Q9UDY2-6	6
Q9UDY2-7	7

RefSeq proteins (11): NP_001163885, NP_001163886, NP_001163887, NP_001356799, NP_001356800, NP_001356801, NP_001356802, NP_001356803, NP_001356804, NP_004808, NP_963923 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR005417	ZO	Family
IPR005419	ZO-2	Family
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035598	ZO-2_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily

Pfam: PF00595, PF00625, PF07653

UniProt features (92 total): modified residue 41, sequence conflict 13, splice variant 7, compositionally biased region 6, sequence variant 6, domain 5, region of interest 5, strand 5, helix 2, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3E17	X-RAY DIFFRACTION	1.75
2OSG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UDY2-F1	62.92	0.28

Functional residue map

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

Post-translational modifications (41): 16, 130, 150, 153, 163, 168, 170, 174, 200, 220, 232, 244, 266, 325, 398, 400, 406, 415, 424, 430 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-351906	Apoptotic cleavage of cell adhesion proteins
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle

MSigDB gene sets: 366 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_DIGESTION, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_ESTABLISHMENT_OF_ENDOTHELIAL_INTESTINAL_BARRIER, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, KEGG_TIGHT_JUNCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, FOXO4_01, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (11): homotypic cell-cell adhesion (GO:0034109), maintenance of blood-brain barrier (GO:0035633), cell-cell junction organization (GO:0045216), intestinal absorption (GO:0050892), establishment of endothelial intestinal barrier (GO:0090557), regulation of membrane permeability (GO:0090559), cell-cell adhesion (GO:0098609), protein localization to cell-cell junction (GO:0150105), positive regulation of blood-brain barrier permeability (GO:1905605), GMP metabolic process (GO:0046037), GDP metabolic process (GO:0046710)

GO Molecular Function (7): GMP kinase activity (GO:0004385), protein domain specific binding (GO:0019904), protein-macromolecule adaptor activity (GO:0030674), cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), cell-cell contact zone (GO:0044291), membrane (GO:0016020), tight junction (GO:0070160), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	1
Apoptotic cleavage of cellular proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
cell-cell junction	3
purine ribonucleotide metabolic process	2
cell-cell adhesion	1
tissue homeostasis	1
cell junction organization	1
digestive system process	1
establishment of endothelial barrier	1
regulation of biological quality	1
cell adhesion	1
protein localization to cell junction	1
positive regulation of vascular permeability	1
regulation of blood-brain barrier permeability	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside diphosphate metabolic process	1
GMP metabolic process	1
GDP metabolic process	1
nucleoside monophosphate kinase activity	1
molecular adaptor activity	1
cell adhesion molecule binding	1
protein kinase binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
cell junction	1

Protein interactions and networks

STRING

1696 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TJP2	CGN	Q9P2M7	999
TJP2	CLDN1	O95832	999
TJP2	OCLN	Q16625	999
TJP2	MARVELD2	Q8N4S9	997
TJP2	CLDN7	O95471	995
TJP2	AFDN	P55196	992
TJP2	CLDN5	O00501	990
TJP2	TJP1	Q07157	988
TJP2	TJP3	O95049	988
TJP2	F11R	Q9Y624	968
TJP2	SAFB	Q15424	957
TJP2	FOS	P01100	927
TJP2	SCRIB	Q14160	909
TJP2	JUN	P05412	909
TJP2	CLDN8	P56748	909

IntAct

834 interactions, top by confidence:

A	B	Type	Score
TJP2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.790
IFI30	DAPK1	psi-mi:“MI:0914”(association)	0.730
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
PRKD1	PRKD3	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
SUMO1	CBX4	psi-mi:“MI:0914”(association)	0.600
TJP2	YAP1	psi-mi:“MI:0407”(direct interaction)	0.590
TAX1BP3	TJP2	psi-mi:“MI:0407”(direct interaction)	0.590
TJP2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.590
TJP2	LASP1	psi-mi:“MI:0915”(physical association)	0.580
LASP1	TJP2	psi-mi:“MI:2364”(proximity)	0.580
LASP1	TJP2	psi-mi:“MI:0914”(association)	0.580
TJP2	LASP1	psi-mi:“MI:0914”(association)	0.580
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
WWTR1	TJP2	psi-mi:“MI:0407”(direct interaction)	0.550
KBTBD7	PLD2	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
IFI30	PRC1	psi-mi:“MI:0914”(association)	0.530
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
TPD52L3	TPD52L2	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (386): TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Affinity Capture-MS), TJP2 (Two-hybrid), LRRC47 (Co-fractionation), TJP2 (Co-fractionation), TJP2 (Co-fractionation), TJP2 (Co-fractionation), TJP2 (Co-fractionation), YWHAQ (Co-fractionation), TJP2 (Biochemical Activity)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TJP2	down-regulates	WWTR1	binding
Cell-Cell_contact	up-regulates	TJP2
TJP2	down-regulates	YAP1	binding
TJP2	“down-regulates activity”	ARVCF	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 222 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	31.1×	5e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	27.4×	8e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	27.4×	8e-06
Activation of BH3-only proteins	7	23.6×	4e-06
Signaling by Hippo	5	18.5×	3e-04
RHO GTPases activate PKNs	7	15.1×	3e-05
Intrinsic Pathway for Apoptosis	7	13.9×	5e-05
Apoptosis	9	10.3×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	27
Uncertain significance	449
Likely benign	183
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030844	NM_004817.4(TJP2):c.2524C>T (p.Gln842Ter)	Pathogenic
1075756	NM_004817.4(TJP2):c.464_473del (p.Gly154_Tyr155insTer)	Pathogenic
1199419	NM_004817.4(TJP2):c.1157del (p.Gln386fs)	Pathogenic
1285612	NM_004817.4(TJP2):c.2645_2646dup (p.Val883fs)	Pathogenic
139628	NM_004817.4(TJP2):c.885del (p.Ser296fs)	Pathogenic
139629	NM_004817.4(TJP2):c.1361del (p.Ala454fs)	Pathogenic
139630	NM_004817.4(TJP2):c.1992-2A>G	Pathogenic
1408745	NM_004817.4(TJP2):c.2546del (p.Thr849fs)	Pathogenic
150050	GRCh38/hg38 9p24.3-q34.3(chr9:193412-138159073)x3	Pathogenic
1705691	NM_004817.4(TJP2):c.2071C>T (p.Gln691Ter)	Pathogenic
1806010	NM_004817.4(TJP2):c.2667+3A>G	Pathogenic
2018080	NM_004817.4(TJP2):c.1880del (p.Arg627fs)	Pathogenic
2026437	NM_004817.4(TJP2):c.766del (p.Ala256fs)	Pathogenic
2026474	NM_004817.4(TJP2):c.2869C>T (p.Gln957Ter)	Pathogenic
217498	NC_000009.12:g.69254209_69254374del	Pathogenic
219195	NM_004817.4(TJP2):c.2668-1G>T	Pathogenic
219196	NM_004817.4(TJP2):c.2438dup (p.Asn814fs)	Pathogenic
219197	NM_004817.4(TJP2):c.817del (p.Ala273fs)	Pathogenic
236063	NC_000009.11:g.71705804_71974823invdup	Pathogenic
2687826	NM_004817.4(TJP2):c.1765C>T (p.Gln589Ter)	Pathogenic
280808	NM_004817.4(TJP2):c.570_574dup (p.Ser192fs)	Pathogenic
282349	NM_004817.4(TJP2):c.1697T>A (p.Leu566Ter)	Pathogenic
2832228	NM_004817.4(TJP2):c.2885del (p.Ile962fs)	Pathogenic
2888023	NM_004817.4(TJP2):c.4_11dup (p.Gly5fs)	Pathogenic
289946	NM_004817.4(TJP2):c.498dup (p.Arg167fs)	Pathogenic
2982875	NM_004817.4(TJP2):c.637C>T (p.Arg213Ter)	Pathogenic
3245329	NC_000009.11:g.(?71831235)(71831399_?)del	Pathogenic
3250406	NM_004817.4(TJP2):c.2624T>C (p.Ile875Thr)	Pathogenic
3662070	NM_004817.4(TJP2):c.903dup (p.Arg302fs)	Pathogenic
3728828	NM_004817.4(TJP2):c.802G>T (p.Glu268Ter)	Pathogenic

SpliceAI

3697 predictions. Top by Δscore:

Variant	Effect	Δscore
9:69212541:A:AG	acceptor_gain	1.0000
9:69212546:A:AC	acceptor_loss	1.0000
9:69212546:A:AG	acceptor_gain	1.0000
9:69212546:AG:A	acceptor_gain	1.0000
9:69212547:G:A	acceptor_loss	1.0000
9:69212547:G:GG	acceptor_gain	1.0000
9:69212547:GG:G	acceptor_gain	1.0000
9:69212599:AAGG:A	donor_loss	1.0000
9:69212600:AGG:A	donor_loss	1.0000
9:69212602:G:GG	donor_gain	1.0000
9:69212603:T:G	donor_loss	1.0000
9:69216329:T:TA	acceptor_gain	1.0000
9:69216335:ACAG:A	acceptor_gain	1.0000
9:69216336:CA:C	acceptor_loss	1.0000
9:69216337:A:AG	acceptor_gain	1.0000
9:69216337:AG:A	acceptor_gain	1.0000
9:69216338:G:A	acceptor_loss	1.0000
9:69216338:G:GG	acceptor_gain	1.0000
9:69216338:GG:G	acceptor_gain	1.0000
9:69216464:G:GG	donor_gain	1.0000
9:69218248:T:TA	acceptor_gain	1.0000
9:69218252:TACA:T	acceptor_loss	1.0000
9:69218253:A:AG	acceptor_gain	1.0000
9:69218254:C:G	acceptor_gain	1.0000
9:69218255:A:AC	acceptor_loss	1.0000
9:69218255:A:AG	acceptor_gain	1.0000
9:69218256:G:GT	acceptor_gain	1.0000
9:69218256:GA:G	acceptor_gain	1.0000
9:69218256:GAGA:G	acceptor_gain	1.0000
9:69218256:GAGAA:G	acceptor_gain	1.0000

AlphaMissense

7817 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:69216354:T:C	F44L	0.999
9:69216356:T:A	F44L	0.999
9:69216356:T:G	F44L	0.999
9:69216358:G:A	G45E	0.999
9:69216367:T:A	V48E	0.999
9:69216373:G:A	G50E	0.999
9:69218331:T:C	L105P	0.999
9:69220891:T:A	V116D	0.999
9:69226095:T:C	L377P	0.999
9:69226101:T:C	L379P	0.999
9:69230135:T:C	L525S	0.999
9:69234491:T:C	L575P	0.999
9:69236151:A:T	D635V	0.999
9:69236180:T:A	W645R	0.999
9:69236180:T:C	W645R	0.999
9:69236950:G:C	A665P	0.999
9:69237893:C:A	P732H	0.999
9:69238755:T:A	V774D	0.999
9:69239953:T:C	L791P	0.999
9:69239983:T:C	L801S	0.999
9:69246773:T:A	W884R	0.999
9:69246773:T:C	W884R	0.999
9:69216352:G:A	G43E	0.998
9:69216355:T:C	F44S	0.998
9:69216357:G:A	G45R	0.998
9:69216357:G:C	G45R	0.998
9:69218319:C:A	A101E	0.998
9:69218322:T:A	V102D	0.998
9:69225313:T:C	L321P	0.998
9:69225403:T:C	L351P	0.998

dbSNP variants (sampled 300 via entrez): RS1000000616 (9:69193675 A>C), RS1000029050 (9:69238146 A>G), RS1000040873 (9:69233734 G>A,C), RS1000051308 (9:69193345 C>T), RS1000056892 (9:69244260 A>G), RS1000063969 (9:69154787 AAATT>A), RS1000077408 (9:69149036 A>G), RS1000112494 (9:69232318 G>A), RS1000132156 (9:69153580 C>A,T), RS1000168943 (9:69180277 T>C), RS1000179637 (9:69149969 G>T), RS1000197979 (9:69227907 A>G), RS1000235581 (9:69227793 A>G), RS1000265316 (9:69227392 C>T), RS1000278942 (9:69186795 C>G)

Disease associations

OMIM: gene MIM:607709 | disease phenotypes: MIM:615878, MIM:607748, MIM:600791, MIM:613558, MIM:109720, MIM:113650

GenCC curated gene-disease

Disease	Classification	Inheritance
cholestasis, progressive familial intrahepatic, 4	Strong	Autosomal recessive
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
familial hypercholanemia	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal dominant
hypercholanemia, familial 1	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (10): cholestasis, progressive familial intrahepatic, 4 (MONDO:0014381), hypercholanemia, familial 1 (MONDO:0031446), hearing loss disorder (MONDO:0005365), autosomal recessive nonsyndromic hearing loss 4 (MONDO:0010933), autosomal dominant nonsyndromic hearing loss 51 (MONDO:0013305), primary biliary cholangitis (MONDO:0005388), branchio-oto-renal syndrome (MONDO:0007029), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), nonsyndromic genetic hearing loss (MONDO:0019497), (MONDO:0011905)

Orphanet (7): Progressive familial intrahepatic cholestasis type 4 (Orphanet:480483), Progressive familial intrahepatic cholestasis type 2 (Orphanet:79304), Familial hypercholanemia (Orphanet:238475), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Primary biliary cholangitis (Orphanet:186), BOR syndrome (Orphanet:107)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000989	Pruritus
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001406	Intrahepatic cholestasis
HP:0001409	Portal hypertension
HP:0001508	Failure to thrive
HP:0002570	Steatorrhea
HP:0002630	Fat malabsorption
HP:0002748	Rickets
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003676	Progressive
HP:0011892	Decreased circulating vitamin K concentration
HP:0012202	Increased serum bile acid concentration

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001304_4	Renal sinus fat	4.000000e-06
GCST001858_23	Refractive error	7.000000e-09
GCST003455_10	Spherical equivalent (joint analysis main effects and education interaction)	2.000000e-09
GCST003455_9	Spherical equivalent (joint analysis main effects and education interaction)	2.000000e-09
GCST003542_111	Night sleep phenotypes	1.000000e-06
GCST003997_29	Myopia	7.000000e-21
GCST006291_138	Spherical equivalent or myopia (age of diagnosis)	1.000000e-21
GCST006976_134	Macular thickness	3.000000e-08
GCST010002_320	Refractive error	3.000000e-39
GCST010007_4	Weight gain in amisulpride-treated first-episode psychosis	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004864	renal sinus adipose tissue measurement
EFO:0004784	self reported educational attainment
EFO:0004847	age at onset
EFO:0005937	longitudinal BMI measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D019280	Branchio-Oto-Renal Syndrome	C16.131.077.208; C16.131.260.090; C16.320.180.090
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008105	Liver Cirrhosis, Biliary	C06.130.120.135.250.250; C06.552.150.250; C06.552.630.400; C23.550.355.412.400
C566366	Deafness, Autosomal Recessive 4 (supp.)
C564336	Hypercholanemia, Familial (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

91 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Benzo(a)pyrene	increases expression, increases methylation, decreases expression, decreases methylation	4
Cisplatin	increases expression, affects expression, affects cotreatment, decreases expression, decreases reaction	4
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, affects expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	decreases expression	2
mercuric bromide	affects cotreatment, increases expression	2
Acetaminophen	increases expression, affects cotreatment, decreases expression	2
Lipopolysaccharides	affects cotreatment, decreases expression, increases expression, affects response to substance	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects phosphorylation, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression, affects cotreatment	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
1,12-benzoperylene	increases expression, affects cotreatment	1
triphenylene	affects cotreatment, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	increases expression	1
benzo(e)pyrene	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound