CLDN2

Summary

CLDN2 (claudin 2, HGNC:2041) is a protein-coding gene on chromosome Xq22.3, encoding Claudin-2 (P57739). Forms paracellular channels: polymerizes in tight junction strands with cation- and water-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.

This gene product belongs to the claudin protein family whose members have been identified as major integral membrane proteins localized exclusively at tight junctions. Claudins are expressed in an organ-specific manner and regulate tissue-specific physiologic properties of tight junctions. This protein is expressed in the intestine. Alternatively spliced transcript variants with different 5’ untranslated region have been found for this gene.

Source: NCBI Gene 9075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary chronic pancreatitis (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 71 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_020384

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2041
Approved symbol	CLDN2
Name	claudin 2
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165376
Ensembl biotype	protein_coding
OMIM	300520
Entrez	9075

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000336803, ENST00000540876, ENST00000541806, ENST00000899662, ENST00000899663, ENST00000899664, ENST00000899665

RefSeq mRNA: 3 — MANE Select: NM_020384 NM_001171092, NM_001171095, NM_020384

CCDS: CCDS14524

Canonical transcript exons

ENST00000336803 — 2 exons

Exon	Start	End
ENSE00001294483	106920402	106920551
ENSE00001362423	106928051	106930861

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 99.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2046 / max 265.1168, expressed in 83 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197172	0.9761	55
197171	0.1192	26
197170	0.1094	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	99.45	gold quality
pancreatic ductal cell	CL:0002079	98.23	silver quality
gall bladder	UBERON:0002110	98.18	gold quality
islet of Langerhans	UBERON:0000006	92.36	gold quality
adult mammalian kidney	UBERON:0000082	92.34	gold quality
right lobe of liver	UBERON:0001114	89.61	gold quality
kidney	UBERON:0002113	88.70	gold quality
adult organism	UBERON:0007023	87.94	gold quality
liver	UBERON:0002107	85.56	gold quality
seminal vesicle	UBERON:0000998	84.44	gold quality
cortex of kidney	UBERON:0001225	84.40	gold quality
ileal mucosa	UBERON:0000331	83.16	silver quality
renal medulla	UBERON:0000362	81.72	gold quality
duodenum	UBERON:0002114	80.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.96	gold quality
caput epididymis	UBERON:0004358	79.76	gold quality
small intestine	UBERON:0002108	78.65	gold quality
pancreas	UBERON:0001264	77.94	gold quality
metanephros cortex	UBERON:0010533	77.14	gold quality
buccal mucosa cell	CL:0002336	76.33	silver quality
body of pancreas	UBERON:0001150	71.45	gold quality
metanephros	UBERON:0000081	70.38	gold quality
pylorus	UBERON:0001166	68.75	gold quality
corpus epididymis	UBERON:0004359	67.65	gold quality
right adrenal gland cortex	UBERON:0035827	66.04	gold quality
left adrenal gland	UBERON:0001234	65.99	gold quality
vermiform appendix	UBERON:0001154	65.61	gold quality
right adrenal gland	UBERON:0001233	65.42	gold quality
adrenal cortex	UBERON:0001235	64.86	gold quality
left adrenal gland cortex	UBERON:0035825	64.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	1080.82
E-MTAB-8495	yes	830.81
E-ANND-3	yes	3.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CDX1, CDX2, CLDN5, CTNNB1, GATA4, GLI1, HNF1A, HNF4A, JUN, LEF1, OCLN, PPARG, TCF4

miRNA regulators (miRDB)

97 targeting CLDN2, 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-8485	100.00	77.57	4731
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-8073	99.86	65.21	1118

Literature-anchored findings (GeneRIF, showing 40)

• identification of eIF4AIII and Barentsz as components of a conserved protein complex that is essential for mRNA localization in flies and nonsense-mediated mRNA decay in mammals (PMID:14973490)
• dIF4A is a maternal-effect suppressor of decapentalplegic. (PMID:15972466)
• eIF4A has a novel function as a specific inhibitor of Dpp signalling that mediates the degradation of SMAD homologues. (PMID:17115029)
• The results suggest that the eIF4A gene is under the control of the DREF pathway and DREF is therefore involved in the regulation of protein synthesis. (PMID:17888422)
• eIF4A controls germline stem cell self-renewal by directly inhibiting BAM function in the Drosophila ovary. (PMID:19556547)
• our data identify the eIF4F complex as an important upstream regulator of TORC1, which acts via TSC2 to inactivate TORC1 upon withdrawal of amino acids (PMID:26988032)
• Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. (PMID:36528028)
• Cloning of the human claudin-2 5’-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1alpha. (PMID:11934881)
• Results support a model in which claudins 2 and 4 create paracellular channels and the first extracellular domain is sufficient to determine both paracellular charge selectivity and transepithelial electrical resistance. (PMID:12700140)
• role for the paracellular barrier function by opening pores for small cations (PMID:14751232)
• optimal claudin-2 expression in the gut relies on the presence of GATA-4, suggesting a role for this factor in intestinal regionalization (PMID:15389642)
• No obvious correlation was found between claudin-2 expression and clinicopathological parameters of colorectal cancers. (PMID:16328347)
• Claudin tight junction proteins in endoscopy biopsy samples showed Barrett’s metaplasia contains more claudin-2 and claudin-3 than found in normal esophageal mucosa, but markedly lower claudins 1 and 5, indicating very different tight junction barriers. (PMID:17103306)
• Expression of claudin-2 was increased in acute calculous cholecystitis. (PMID:17283368)
• RT-PCR data show high expression of putative tumor suppressor genes Rsk4 and RbAp46 in 47% and 79% of breast carcinoma cases, respectively, whereas Cldn2 was down-regulated in 52% of breast cancer cases compared with normal adjacent tissues. (PMID:17314274)
• Comparison of adenocarcinomas and squamous cell carcinomas revealed significant differences in CLDN2 expression. (PMID:17418912)
• IL-4 and interferon gamma have opposite effects on the expression of claudin-2 and the physiology of the tight junction (PMID:17640674)
• The expression of claudin-1 and claudin-2 in cancer tissues was upregulated 40- and 49.2-fold, respectively, at the mRNA level, as compared with that in normal tissues (PMID:17970035)
• Expression of claudin-2 results in a selective increase in pore number but not size and has no effect on the permeability of PEGs that are larger than the pores. (PMID:18198187)
• These findings strongly suggest that claudin-2- and/or claudin-12-based tight junctions form paracellular Ca(2+) channels in intestinal epithelia, and they highlight a novel mechanism behind vitamin D-dependent calcium homeostasis. (PMID:18287530)
• Claudin-2 protein overexpression may be closely correlated to gastric carcinogenesis. (PMID:18366005)
• Significant correlations sre found between claudin-2 and Cdx2 protein expression in dysplasia and intestine-type adenocarcinoma. (PMID:18500171)
• The discovery of claudin 2 transcript and protein in the skin could be of importance in epidermal differentiation, barrier function and pathological conditions. (PMID:18509255)
• These results provide an insight into the changes in the inter-molecular forces and adhesion kinetics of Cldn2 mediated interactions in acidic, neutral and alkaline environments. (PMID:18602630)
• Claudin-1 and claudin-2 expression was elevated in active inflammatory bowel disease (IBD), adenomas, and IBD-associated dysplasia, but not acute self limiting colitis (PMID:18711353)
• findings are consistent with the hypothesis that EGFR signaling plays an important role in A549 cell physiology and acts synergistically with claudin-2 to accelerate tumor colonizati (PMID:18942115)
• The expression of claudins-2, -3 and -4 in 16 rectal well-differentiated endocrine neoplasms was studied (PMID:19082451)
• Up-regulation of claudin-2 might lead to altered tight junction structure and be related to the impaired epithelial function in active ulcerative colitis. (PMID:19120888)
• The up-regulation of claudin-2 by TNFalpha is attributable to the regulation of the expression of the gene, as a result of which epithelial barrier function is disturbed. (PMID:19214581)
• Data show that claudin-2 expression was reduced following symplekin down-regulation, and siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization. (PMID:20133805)
• CLDN 2 expression was significantly increased in severe form of coeliac disease in bulb and in distal duodenum (PMID:20143085)
• claudin-2 was not expressed in any of the 18 cases of Epstein-Barr virus-associated nasopharyngeal carcinoma studied. (PMID:20204275)
• The authors propose claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4 T-cell depletion in HIV-1-infected patients. (PMID:20700059)
• CLDN2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of cell membrane complexes. (PMID:21076473)
• demonstrate here that breast cancer cells harbouring PIK3CA mutations are selectively sensitive to mTOR allosteric and kinase inhibitors. However, cells with PTEN loss of function are not sensitive to these drugs (PMID:21383692)
• Pore-forming tight junction protein claudin-2 is strongly expressed in the ileum of 51% patients in quiescent phase and in 49% of the patients with active Crohn’s disease. (PMID:21688348)
• These results suggest that EGF is secreted from A549 cells by MMP and increases claudin-2 expression mediated via the activation of an EGFR/MEK/ERK pathway. (PMID:22546605)
• Stable expression of inducible GFP-SUMO-1 in MDCK cells resulted in decreased levels of claudin-2 protein by immunoblot and decreased claudin-2 membrane expression (PMID:22731716)
• Sinonasal epithelium in allergic fungal rhinosinusitis displays increased epithelial permeability and an altered expression of claudin-2 (PMID:22927233)
• results implicate pericryptal myofibroblast-derived paracrine KGF and largely autocrine amphiregulin in the upregulation of claudin-2 in Caco-2 epithelial monolayers and consequent disruption of tight junction integrity (PMID:22946653)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cldn2	ENSDARG00000044387
mus_musculus	Cldn2	ENSMUSG00000047230
rattus_norvegicus	Cldn2	ENSRNOG00000054495

Paralogs (22): CLDN11 (ENSG00000013297), CLDN18 (ENSG00000066405), CLDN15 (ENSG00000106404), CLDN16 (ENSG00000113946), CLDN10 (ENSG00000134873), CLDN17 (ENSG00000156282), CLDN8 (ENSG00000156284), CLDN14 (ENSG00000159261), CLDN1 (ENSG00000163347), CLDN19 (ENSG00000164007), CLDN3 (ENSG00000165215), CLDN20 (ENSG00000171217), CLDN22 (ENSG00000177300), CLDN7 (ENSG00000181885), CLDN5 (ENSG00000184113), CLDN6 (ENSG00000184697), CLDN24 (ENSG00000185758), CLDN4 (ENSG00000189143), CLDN9 (ENSG00000213937), CLDN25 (ENSG00000228607), CLDN34 (ENSG00000234469), CLDN23 (ENSG00000253958)

Protein

Protein identifiers

Claudin-2 — P57739 (reviewed: P57739)

Alternative names: SP82

All UniProt accessions (1): P57739

UniProt curated annotations — full annotation on UniProt →

Function. Forms paracellular channels: polymerizes in tight junction strands with cation- and water-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability. In intestinal epithelium, allows for sodium and water fluxes from the peritoneal side to the lumen of the intestine to regulate nutrient absorption and clear enteric pathogens as part of mucosal immune response. In kidney, allows passive sodium and calcium reabsorption across proximal tubules from the lumen back to the bloodstream. In the hepatobiliary tract, allows paracellular water and cation fluxes in the hepatic perivenous areas and biliary epithelium to generate bile flow and maintain osmotic gradients.

Subunit / interactions. Can form homo- and heteropolymers with other claudins to mediate paracellular barrier and channel functions of tight junctions in response to physiological stimuli. Homopolymers interact with CLDN3, but not CLDN1, homopolymers. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3.

Subcellular location. Cell junction. Tight junction. Cell membrane.

Post-translational modifications. The disulfide bond is necessary for pore formation, but is not required for correct protein trafficking.

Disease relevance. Azoospermia, obstructive, with nephrolithiasis (OAZON) [MIM:301060] An X-linked recessive, male infertility disorder characterized by epidydimal obstruction, hypercalciuria and kidney stones. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the claudin family.

RefSeq proteins (3): NP_001164563, NP_001164566, NP_065117* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR005411	Claudin2	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

Catalyzed reactions (Rhea), 9 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• H2O(in) = H2O(out) (RHEA:29667)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• choline(out) = choline(in) (RHEA:32751)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• methylamine(out) = methylamine(in) (RHEA:74391)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Li(+)(in) = Li(+)(out) (RHEA:78551)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (21 total): topological domain 5, transmembrane region 4, region of interest 2, modified residue 2, chain 1, compositionally biased region 1, site 1, disulfide bond 1, cross-link 1, sequence variant 1, helix 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4YYX	X-RAY DIFFRACTION	1.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57739-F1	78.99	0.42

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): 65 (paracellular cation selectivity)

Post-translational modifications (3): 219, 223, 218

Disulfide bonds (1): 54–64

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 143 (showing top): GOBP_DIGESTION, GOBP_ACID_SECRETION, HNF3ALPHA_Q6, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, XU_GH1_AUTOCRINE_TARGETS_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, KEGG_TIGHT_JUNCTION, FOXO1_01, CAGCTG_AP4_Q5, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE, RODRIGUES_NTN1_TARGETS_DN, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_CELL_CELL_ADHESION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (8): innate immune response in mucosa (GO:0002227), calcium-independent cell-cell adhesion (GO:0016338), bicellular tight junction assembly (GO:0070830), cell-cell adhesion (GO:0098609), regulation of bile acid secretion (GO:0120188), paracellular transport (GO:0160184), regulation of intestinal D-glucose absorption (GO:1903985), regulation of intestinal lipid absorption (GO:1904729)

GO Molecular Function (4): structural molecule activity (GO:0005198), identical protein binding (GO:0042802), paracellular tight junction channel activity (GO:0160187), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), cell junction (GO:0030054), tight junction (GO:0070160), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-cell junction organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of intestinal absorption	2
mucosal immune response	1
innate immune response	1
cell-cell adhesion	1
apical junction assembly	1
tight junction assembly	1
cell adhesion	1
bile acid secretion	1
regulation of organic acid transport	1
regulation of secretion	1
transport	1
intestinal D-glucose absorption	1
intestinal lipid absorption	1
molecular_function	1
protein binding	1
transporter activity	1
binding	1
nuclear lumen	1
membrane	1
cell periphery	1
anchoring junction	1
apical junction complex	1
tight junction	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

1062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN2	TJP1	Q07157	967
CLDN2	OCLN	Q16625	958
CLDN2	CLDN12	P56749	934
CLDN2	TJP2	Q9UDY2	884
CLDN2	TJP3	O95049	879
CLDN2	MARVELD2	Q8N4S9	793
CLDN2	F11R	Q9Y624	664
CLDN2	CDX1	P47902	599
CLDN2	CDX2	Q99626	599
CLDN2	MPDZ	O75970	591
CLDN2	CDH1	P12830	587
CLDN2	STIP1	P31948	585
CLDN2	CGN	Q9P2M7	571
CLDN2	TRIM21	P19474	568
CLDN2	HSP90B1	P14625	565

IntAct

185 interactions, top by confidence:

A	B	Type	Score
	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
KRT31	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	KRT31	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	KRTAP1-1	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	CLEC2D	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	GRM2	psi-mi:“MI:0915”(physical association)	0.560
EMP3	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	ADAM33	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	BTN3A2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	TEX264	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	PLP1	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	CSGALNACT2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	CXCL9	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	IL27RA	psi-mi:“MI:0915”(physical association)	0.560
LAT	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	CLDN2	psi-mi:“MI:0915”(physical association)	0.560
CLDN2	TJP1	psi-mi:“MI:0403”(colocalization)	0.550
CLDN2	TJP1	psi-mi:“MI:0407”(direct interaction)	0.550
AP2M1	CLDN2	psi-mi:“MI:0914”(association)	0.540

BioGRID (32): CLDN2 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), KRTAP4-12 (Two-hybrid), CLDN2 (Protein-RNA), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid), CLDN2 (Two-hybrid)

ESM2 similar proteins: A6NFC5, A6NM45, A8MUP6, B1AQL3, C3VMW3, C9JDP6, O35912, O75204, O88551, O88552, O95500, O95832, P56745, P56746, P56748, P56750, P57739, Q08DE1, Q0V9E0, Q0VCN0, Q16617, Q2KIY2, Q2KJ11, Q3UUA0, Q4V922, Q5CZV0, Q5M962, Q5QT56, Q6ICI0, Q765P1, Q7T392, Q7TQI0, Q7Z7N9, Q8BGP5, Q8BXA6, Q8N7P3, Q8NHS1, Q8VHW3, Q95KM6, Q96B33

Diamond homologs: A0A8C0N7E5, A6NM45, C3VMW3, C9JDP6, D3ZQJ0, O00501, O14493, O15551, O19005, O35054, O54942, O75508, O88551, O88552, O95471, O95484, O95500, O95832, P56745, P56746, P56747, P56748, P56750, P56856, P56857, P56880, P57739, P78369, Q0VCN0, Q2HJ22, Q2KIY2, Q3B7N4, Q3MHK4, Q4R3L1, Q5E9L0, Q5I0E5, Q5QT56, Q5R8E5, Q60771, Q63400

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CTNNB1	“up-regulates quantity by expression”	CLDN2	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	CLDN2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Trafficking of GluR2-containing AMPA receptors	5	48.7×	3e-06
Ras activation upon Ca2+ influx through NMDA receptor	5	41.4×	6e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	39.4×	6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	39.4×	6e-06
Assembly and cell surface presentation of NMDA receptors	10	36.8×	1e-11
Dopamine Neurotransmitter Release Cycle	5	36.0×	8e-06
Long-term potentiation	5	34.5×	9e-06
Neurexins and neuroligins	11	31.4×	9e-12

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	68.0×	2e-15
protein localization to synapse	6	48.9×	3e-07
receptor clustering	7	46.5×	3e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	36.9×	1e-07
protein-containing complex assembly	10	12.1×	1e-06
cell-cell adhesion	10	10.8×	3e-06
chemical synaptic transmission	10	8.2×	2e-05
intracellular signal transduction	10	4.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	25
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
488651	NM_020384.4(CLDN2):c.481G>C (p.Gly161Arg)	Pathogenic
2506548	GRCh37/hg19 Xq22.3(chrX:105066840-106486528)	Likely pathogenic

SpliceAI

945 predictions. Top by Δscore:

Variant	Effect	Δscore
X:106900328:G:GT	donor_gain	0.9900
X:106900907:GC:G	acceptor_gain	0.9900
X:106900907:GCCTG:G	acceptor_loss	0.9900
X:106900908:CC:C	acceptor_gain	0.9900
X:106900908:CCTG:C	acceptor_loss	0.9900
X:106900909:C:CC	acceptor_gain	0.9900
X:106900910:T:G	acceptor_loss	0.9900
X:106902598:T:TA	donor_gain	0.9900
X:106903129:TTAC:T	donor_loss	0.9800
X:106903130:TA:T	donor_loss	0.9800
X:106903131:A:AC	donor_gain	0.9800
X:106903131:A:T	donor_loss	0.9800
X:106903132:C:CC	donor_gain	0.9800
X:106903132:C:CG	donor_loss	0.9800
X:106903132:CCTTT:C	donor_gain	0.9800
X:106928046:TTTA:T	acceptor_loss	0.9800
X:106928047:TTA:T	acceptor_loss	0.9800
X:106928048:TA:T	acceptor_loss	0.9800
X:106928049:A:AG	acceptor_gain	0.9800
X:106928049:A:AT	acceptor_loss	0.9800
X:106928050:G:GG	acceptor_gain	0.9800
X:106928050:G:GT	acceptor_loss	0.9800
X:106900905:GAGC:G	acceptor_gain	0.9700
X:106903151:T:TA	donor_gain	0.9700
X:106901602:C:CC	acceptor_gain	0.9600
X:106902216:C:CC	acceptor_gain	0.9600
X:106921356:A:T	donor_gain	0.9600
X:106928050:GGT:G	acceptor_gain	0.9600
X:106928050:GGTC:G	acceptor_gain	0.9600
X:106900904:AGAGC:A	acceptor_gain	0.9500

AlphaMissense

1480 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:106928318:G:C	W30C	0.997
X:106928318:G:T	W30C	0.997
X:106928418:T:A	C64S	0.996
X:106928419:G:C	C64S	0.996
X:106928373:G:C	G49R	0.995
X:106928381:G:C	W51C	0.995
X:106928381:G:T	W51C	0.995
X:106928316:T:A	W30R	0.994
X:106928316:T:C	W30R	0.994
X:106928388:T:A	C54S	0.994
X:106928389:G:C	C54S	0.994
X:106928268:G:C	G14R	0.993
X:106928277:G:A	G17R	0.992
X:106928277:G:C	G17R	0.992
X:106928373:G:T	G49C	0.992
X:106928667:T:C	F147L	0.992
X:106928669:C:A	F147L	0.992
X:106928669:C:G	F147L	0.992
X:106928761:G:A	G178E	0.992
X:106928379:T:A	W51R	0.991
X:106928379:T:C	W51R	0.991
X:106928710:G:T	G161V	0.991
X:106928388:T:C	C54R	0.990
X:106928418:T:C	C64R	0.990
X:106928613:G:C	G129R	0.990
X:106928760:G:A	G178R	0.990
X:106928760:G:C	G178R	0.990
X:106928269:G:A	G14D	0.989
X:106928377:T:A	L50H	0.989
X:106928511:T:C	C95R	0.988

dbSNP variants (sampled 300 via entrez): RS1000070618 (X:106904302 C>T), RS1000444978 (X:106930948 G>A), RS1000505782 (X:106903857 G>A,T), RS1001343384 (X:106927194 C>T), RS1001366337 (X:106911986 C>T), RS1001571426 (X:106904892 G>A), RS1001587558 (X:106901658 G>T), RS1001684744 (X:106914019 C>A), RS1001763552 (X:106921928 A>T), RS1001837561 (X:106921515 C>T), RS1002114299 (X:106913764 C>A), RS1002208261 (X:106903950 T>C), RS1002344291 (X:106898590 G>A,C), RS1002385586 (X:106914593 T>C), RS1002500692 (X:106907665 C>T)

Disease associations

OMIM: gene MIM:300520 | disease phenotypes: MIM:244400, MIM:301060

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary chronic pancreatitis	Limited	Autosomal dominant
azoospermia, obstructive, with nephrolithiasis	Limited	Unknown

Mondo (4): primary ciliary dyskinesia (MONDO:0016575), male infertility (MONDO:0005372), azoospermia, obstructive, with nephrolithiasis (MONDO:0025356), hereditary chronic pancreatitis (MONDO:0008185)

Orphanet (1): Primary ciliary dyskinesia (Orphanet:244)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000787	Nephrolithiasis
HP:0001419	X-linked recessive inheritance
HP:0003251	Male infertility
HP:0011962	Obstructive azoospermia
HP:0033808	Spermatocele

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001741_2	Pancreatitis	2.000000e-22
GCST004860_73	Alcoholic chronic pancreatitis	2.000000e-29
GCST004860_77	Alcoholic chronic pancreatitis	6.000000e-15

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
C537262	Hereditary pancreatitis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Aflatoxin B1	increases expression, decreases methylation	2
Okadaic Acid	increases expression	2
aristolochic acid I	decreases expression	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
sanguinarine	decreases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases methylation	1
acadesine	increases reaction, decreases expression	1
solasodine	decreases expression, increases reaction, decreases reaction, increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	decreases expression	1
potassium bromate	decreases expression	1
ochratoxin A	decreases expression	1
diallyl disulfide	decreases expression	1
diallyl trisulfide	decreases expression	1
brequinar	decreases expression	1
caffeic acid phenethyl ester	increases activity, increases response to substance, decreases expression, decreases reaction	1
cordycepin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
6-formylindolo(3,2-b)carbazole	decreases reaction, increases expression, affects reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
Resveratrol	decreases expression, decreases reaction, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3V8	HT-1080/hCLDN-2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT00830557	Not specified	RECRUITING	Collecting Medical Information and Tissue Samples From Patients With Pancreatic Cancer or Other Pancreatic Disorders
NCT02078245	Not specified	UNKNOWN	Quality Control Study of MR Based Screening of Individual With Increased Risk for Pancreas Cancer.
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT02309632	Not specified	WITHDRAWN	Pancreatic Cancer Screening of High-Risk Individuals in Arkansas
NCT04095195	Not specified	RECRUITING	Registry of Subjects at Risk of Pancreatic Cancer
NCT04743479	Not specified	RECRUITING	Artificial Intelligence-based Early Screening of Pancreatic Cancer and High Risk Tracing (ESPRIT-AI)
NCT07413029	Not specified	RECRUITING	French National Cohort of Patients With PRSS1 Mutations
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide