CLDN18

Summary

CLDN18 (claudin 18, HGNC:2039) is a protein-coding gene on chromosome 3q22.3, encoding Claudin-18 (P56856). Involved in alveolar fluid homeostasis via regulation of alveolar epithelial tight junction composition and therefore ion transport and solute permeability, potentially via downstream regulation of the actin cytoskeleton organization and beta-2-adrenergic signaling.

This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This gene is upregulated in patients with ulcerative colitis and highly overexpressed in infiltrating ductal adenocarcinomas. PKC/MAPK/AP-1 (protein kinase C/mitogen-activated protein kinase/activator protein-1) dependent pathway regulates the expression of this gene in gastric cells. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 51208 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 43 total
• Druggable target: yes
• MANE Select transcript: NM_016369

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2039
Approved symbol	CLDN18
Name	claudin 18
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000066405
Ensembl biotype	protein_coding
OMIM	609210
Entrez	51208

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000183605, ENST00000343735, ENST00000479660, ENST00000862384, ENST00000956271

RefSeq mRNA: 2 — MANE Select: NM_016369 NM_001002026, NM_016369

CCDS: CCDS3095, CCDS33862

Canonical transcript exons

ENST00000183605 — 5 exons

Exon	Start	End
ENSE00000778670	138023658	138023822
ENSE00000778672	138024607	138024724
ENSE00001546979	138030970	138033649
ENSE00001919606	138010165	138010445
ENSE00003518647	138029797	138029907

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 99.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7461 / max 916.3209, expressed in 53 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38765	0.7997	29
38769	0.5791	17
38770	0.1173	9
38768	0.0862	9
38766	0.0695	9
38764	0.0628	12
38767	0.0315	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	99.82	gold quality
lower lobe of lung	UBERON:0008949	99.16	gold quality
cardia of stomach	UBERON:0001162	99.09	gold quality
right lung	UBERON:0002167	97.79	gold quality
lung	UBERON:0002048	96.06	gold quality
adult organism	UBERON:0007023	95.94	gold quality
upper lobe of lung	UBERON:0008948	95.61	gold quality
upper lobe of left lung	UBERON:0008952	95.36	gold quality
stomach	UBERON:0000945	91.64	gold quality
body of stomach	UBERON:0001161	90.69	gold quality
mucosa of stomach	UBERON:0001199	89.41	gold quality
visceral pleura	UBERON:0002401	88.39	gold quality
fundus of stomach	UBERON:0001160	87.86	gold quality
oocyte	CL:0000023	87.53	gold quality
secondary oocyte	CL:0000655	85.58	gold quality
pancreatic ductal cell	CL:0002079	83.91	silver quality
epithelium of nasopharynx	UBERON:0001951	76.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.17	silver quality
buccal mucosa cell	CL:0002336	73.87	silver quality
paraflocculus	UBERON:0005351	72.95	gold quality
middle frontal gyrus	UBERON:0002702	72.65	gold quality
gall bladder	UBERON:0002110	71.25	gold quality
epithelial cell of pancreas	CL:0000083	69.89	silver quality
olfactory bulb	UBERON:0002264	69.31	gold quality
type B pancreatic cell	CL:0000169	69.25	gold quality
endometrium epithelium	UBERON:0004811	68.71	gold quality
thymus	UBERON:0002370	68.28	gold quality
pleura	UBERON:0000977	68.12	gold quality
tongue squamous epithelium	UBERON:0006919	67.65	gold quality
trachea	UBERON:0003126	66.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	25.46
E-GEOD-130148	yes	13.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

109 targeting CLDN18, 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-4533	100.00	69.48	2758
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3681-3P	99.88	70.46	2254

Literature-anchored findings (GeneRIF, showing 40)

• Loss of claudin expression may enhance the grade of malignancy of gastric cancer in vivo. (PMID:17459057)
• We conclude that Cldn-18 is the dominant claudin in the TJ of SCE and propose that the change from a Cldn-18-deficient TJ in SqE to a Cldn-18-rich TJ in SCE contributes to the greater acid resistance of BE. (PMID:17932229)
• Indicate that the PKC/MAPK/AP-1 dependent pathway regulates claudin-18a2 expression in gastric cells. (PMID:18032479)
• Claudin 18 and annexin A8 are frequently highly overexpressed in infiltrating ductal adenocarcinomas. (PMID:18223320)
• Claudin 18 staining can aid in diagnosis of gastrointestinal signet ring cell carcinoma. (PMID:18580680)
• Increased expression of claudin-18 is associated with colitis. (PMID:18831034)
• CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors. (PMID:19047087)
• We revealed that claudin-18 expression correlates with poor survival in patients with colorectal cancer and is associated with the gastric phenotype. (PMID:20846265)
• High claudin 18 is associated with intraductal papillary mucinous neoplasms of the pancreas. (PMID:21206985)
• Cldn18 is primarily regulated at the transcriptional level via specific protein kinase C signaling pathways and modified by DNA methylation (PMID:21381080)
• These results suggest that CLDN18 may play an important role in biliary carcinogenesis. (PMID:21607649)
• Claudin 18 (a marker for early carcinogenesis) is commonly expressed in precursor lesions of pancreatic ductal adenocarcinomas. Activation of the protein kinase C pathway might be involved in claudin 18 expression associated with carcinogenesis. (PMID:21832145)
• Claudin 10/18 are most commonly expressed in lung adenocarcinomas. Female patients and non-smokers express these claudins more commonly suggesting that they may play a part in the carcinogenesis of tobacco unrelated carcinoma. (PMID:22076167)
• Reduced expression of olfactomedin 4 and ectopic expression of claudin-18 might be useful markers in the differential diagnosis of serrated polyps. (PMID:23570326)
• rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis (PMID:23900716)
• Claudin-18 positivity is a specific phenotype that is characteristic of intestinal-type Mucinous borderline tumours of the ovary (PMID:23905715)
• Down-regulation of claudin-18 is associated with the proliferative and invasive potential of gastric cancer. (PMID:24073219)
• Evaluated expression of claudins in gastric cancer and determined their significance for patient outcome. Claudin-3 and claudin-7 were expressed in 25.4% and 29.9% of gastric cancer tissues; 51.5% of gastric cancer tissues had reduced claudin-18. (PMID:24333468)
• Downregulation of miR-1303 can inhibit proliferation, migration and invasion of gastric cancer cells by targeting CLDN18. (PMID:24647998)
• High levels of CLDN18 are associated with non-small-cell lung cancer. (PMID:24710653)
• Human fetal lungs at 23-24 weeks gestational age, the highest-risk period for developing bronchopulmonary dysplasia, a disease of impaired alveolarization, had significantly lower CLDN18 expression relative to postnatal lungs. (PMID:24787463)
• Data suggest that claudin-18 suppresses the abnormal proliferation and motility of lung epithelial cells mediated by inhibition of phosphorylation of pyruvate dehydrogenase kinase isoform 1 (PDK1) and proto-oncogene protein c-akt (Akt). (PMID:26919807)
• The presented data substantiate the hypothesis that claudin-18 is a central barrier-forming component of tight junctions and show that IL-13 downregulates claudin-18. These data also suggest that the loss of claudin-18 is associated with increased sensitization to aeroantigens and airway responsiveness (PMID:27215490)
• CDH17 and CLDN18 are useful target molecules. Their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity. (PMID:27580354)
• suggest that the reduction of CLDN5, 7, and 18 expression loses the suppressive ability of interaction between PDK1 and Akt and causes sustained phosphorylation of Akt, resulting in the disordered proliferation in lung squamous carcinoma cells (PMID:27884700)
• Bile duct adenocarcinoma cells overexpress claudin-18 via the EGFR/RAS/ERK pathway, contributing to cell proliferation and invasion. (PMID:28624624)
• In this study, we found downregulation of miR-767-3p and upregulation of CLDN18 in lung adenocarcinoma tissue and cell lines. (PMID:29169410)
• data indicate a tumor suppressor role for CLDN18.1 in LuAd mediated by a regulatory network that encompasses YAP/TAZ, IGF-1R and AKT signaling (PMID:30325015)
• present study showed that intestinal-type adenocarcinoma with anastomosing glands represents a genetically distinct group of tumors with the frequent presence of RHOA mutations and CLDN18-ARHGAP fusions (PMID:30425335)
• CLDN18 is a new metaplasia marker in gallbladder tissues, and is conserved in approximately half of gallbladder cancer cases (PMID:30565710)
• 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)
• These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age-onset gastric cancers, and its presence could contribute to their aggressive characteristics. (PMID:30771244)
• Higher expression of CLDN18.2 was observed in diffuse-type and HER2-positive gastric cancers. Meanwhile, CLDN18.2 expression was not associated with survival in patients with gastric cancer. (PMID:31810969)
• immunophenotyping with CLDN18, CDH17, and PAX8 might improve the diagnostic accuracy of histopathological classifications of endocervical adenocarcinoma (PMID:31932920)
• Analysis of the expression and genetic alteration of CLDN18 in gastric cancer. (PMID:32668412)
• Claudin-18 as a Marker for Identifying the Stomach and Pancreatobiliary Tract as the Primary Sites of Metastatic Adenocarcinoma. (PMID:32925194)
• Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. (PMID:33590909)
• [A review on the effect of Claudin-18 on bronchopulmonary dysplasia in preterm infants]. (PMID:34020748)
• Gastric Cancer CAR T-cell Target Antigen ID’d. (PMID:34642170)
• Claudin-18 as a Promising Surrogate Marker for Endocervical Gastric-type Carcinoma. (PMID:34864774)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cldn18	ENSDARG00000103087
mus_musculus	Cldn18	ENSMUSG00000032473
rattus_norvegicus	Cldn18	ENSRNOG00000030386

Paralogs (22): CLDN11 (ENSG00000013297), CLDN15 (ENSG00000106404), CLDN16 (ENSG00000113946), CLDN10 (ENSG00000134873), CLDN17 (ENSG00000156282), CLDN8 (ENSG00000156284), CLDN14 (ENSG00000159261), CLDN1 (ENSG00000163347), CLDN19 (ENSG00000164007), CLDN3 (ENSG00000165215), CLDN2 (ENSG00000165376), 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-18 — P56856 (reviewed: P56856)

All UniProt accessions (2): P56856, F8WEY4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in alveolar fluid homeostasis via regulation of alveolar epithelial tight junction composition and therefore ion transport and solute permeability, potentially via downstream regulation of the actin cytoskeleton organization and beta-2-adrenergic signaling. Required for lung alveolarization and maintenance of the paracellular alveolar epithelial barrier. Acts to maintain epithelial progenitor cell proliferation and organ size, via regulation of YAP1 localization away from the nucleus and thereby restriction of YAP1 target gene transcription. Acts as a negative regulator of RANKL-induced osteoclast differentiation, potentially via relocation of TJP2/ZO-2 away from the nucleus, subsequently involved in bone resorption in response to calcium deficiency. Mediates the osteoprotective effects of estrogen, potentially via acting downstream of estrogen signaling independently of RANKL signaling pathways. Involved in the maintenance of homeostasis of the alveolar microenvironment via regulation of pH and subsequent T-cell activation in the alveolar space, is therefore indirectly involved in limiting C.neoformans infection. Required for the formation of the gastric paracellular barrier via its role in tight junction formation, thereby involved in the response to gastric acidification.

Subunit / interactions. Interacts with TJP2/ZO-2. Interacts with TJP1/ZO-1. Interacts with YAP1 (phosphorylated); the interaction sequesters YAP1 away from the nucleus and thereby restricts transcription of YAP1 target genes. Interacts with CLDN19.

Subcellular location. Cell junction. Tight junction. Cell membrane Cell junction. Tight junction Cell junction. Lateral cell membrane.

Tissue specificity. Expression is restricted to the lung. Expression is restricted to the stomach mucosa where it is predominantly observed in the epithelial cells of the pit region and the base of the gastric glands including exocrine and endocrine cells (at protein level).

Similarity. Belongs to the claudin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56856-1	A1, CLDN18.1	yes
P56856-2	A2, CLDN18.2

RefSeq proteins (2): NP_001002026, NP_057453* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003928	Claudin18	Family
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

UniProt features (15 total): topological domain 5, transmembrane region 4, region of interest 2, chain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9V2U	ELECTRON MICROSCOPY	3.8
9V32	ELECTRON MICROSCOPY	4.1
9V31	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56856-F1	72.21	0.29

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 (1): 214

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 178 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_GROWTH, GOBP_BONE_CELL_DEVELOPMENT, KEGG_TIGHT_JUNCTION, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (16): cell adhesion (GO:0007155), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), calcium-independent cell-cell adhesion (GO:0016338), protein localization to nucleus (GO:0034504), organ growth (GO:0035265), epithelial fluid transport (GO:0042045), response to ethanol (GO:0045471), negative regulation of bone resorption (GO:0045779), lung alveolus development (GO:0048286), digestive tract development (GO:0048565), epithelial cell proliferation (GO:0050673), bicellular tight junction assembly (GO:0070830), cellular response to estrogen stimulus (GO:0071391), tight junction organization (GO:0120193), negative regulation of protein localization to nucleus (GO:1900181), negative regulation of osteoclast development (GO:2001205)

GO Molecular Function (3): structural molecule activity (GO:0005198), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), lateral plasma membrane (GO:0016328), membrane (GO:0016020), tight junction (GO:0070160), 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	2
cellular process	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cell-cell adhesion	1
protein localization to organelle	1
multicellular organismal process	1
developmental growth	1
fluid transport	1
transepithelial transport	1
response to alcohol	1
regulation of bone resorption	1
bone resorption	1
negative regulation of bone remodeling	1
lung development	1
anatomical structure development	1
tube development	1
digestive system development	1
cell population proliferation	1
apical junction assembly	1
tight junction assembly	1
cellular response to hormone stimulus	1
response to estrogen	1
cell-cell junction organization	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
negative regulation of protein localization	1
osteoclast development	1
negative regulation of osteoclast differentiation	1
regulation of osteoclast development	1
molecular_function	1
protein binding	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
apical junction complex	1
tight junction	1
plasma membrane	1

Protein interactions and networks

STRING

724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN18	NKX2-1	P43699	822
CLDN18	ARHGAP26	Q9UNA1	708
CLDN18	YAP1	P46937	636
CLDN18	CDH1	P12830	616
CLDN18	ARHGAP6	O43182	595
CLDN18	CLDN12	P56749	568
CLDN18	OCLN	Q16625	525
CLDN18	TJP1	Q07157	506
CLDN18	CLDN15	P56746	497
CLDN18	REG4	Q9BYZ8	477
CLDN18	VSIG1	Q86XK7	461
CLDN18	RHOA	P06749	460
CLDN18	TJP2	Q9UDY2	454
CLDN18	EPCAM	P16422	452
CLDN18	ERBB2	P04626	451

IntAct

109 interactions, top by confidence:

A	B	Type	Score
CLDN18	PMP22	psi-mi:“MI:0915”(physical association)	0.560
CLDN18	EHHADH	psi-mi:“MI:0915”(physical association)	0.560
CLDN18	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	NOS1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
HTRA3	CLDN18	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
GORASP2	CLDN18	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	CLDN18	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	MPDZ	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
DLG5	CLDN18	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN18	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (7): THEM4 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), PMP22 (Two-hybrid), EHHADH (Two-hybrid), THEM4 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), S (Reconstituted Complex)

ESM2 similar proteins: C3VMW3, D3ZQJ0, O00501, O54942, O75508, O88551, O88552, O95471, O95500, O95832, P56745, P56746, P56747, P56748, P56750, P56856, P56857, P57739, Q0VCN0, Q2HJ22, Q2KIY2, Q3B7N4, Q3MHK4, Q4KL25, Q4R3L1, Q5I0E5, Q5PPI7, Q5QT56, Q5REK8, Q60771, Q6DHP1, Q6L708, Q765P1, Q8BXA6, Q8N6F1, Q8NG11, Q8TAF8, Q95KM6, Q99P82, Q9ET38

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 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
Ras activation upon Ca2+ influx through NMDA receptor	5	58.3×	8e-07
Unblocking of NMDA receptors, glutamate binding and activation	5	55.5×	8e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	5	55.5×	8e-07
Assembly and cell surface presentation of NMDA receptors	10	51.8×	5e-13
Dopamine Neurotransmitter Release Cycle	5	50.7×	1e-06
Long-term potentiation	5	48.5×	1e-06
Neurexins and neuroligins	10	40.2×	4e-12
Protein-protein interactions at synapses	6	32.5×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	81.8×	8e-15
protein localization to synapse	6	64.7×	5e-08
receptor clustering	7	61.5×	3e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	41.9×	4e-07
cell-cell adhesion	10	14.3×	2e-07
protein-containing complex assembly	8	12.8×	1e-05
protein localization to plasma membrane	5	7.7×	8e-03
chemical synaptic transmission	7	7.6×	1e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

601 predictions. Top by Δscore:

Variant	Effect	Δscore
3:138023656:A:AG	acceptor_gain	1.0000
3:138023657:G:GG	acceptor_gain	1.0000
3:138023657:GCC:G	acceptor_gain	1.0000
3:138023818:CTCAG:C	donor_loss	1.0000
3:138023819:TCAGG:T	donor_loss	1.0000
3:138023820:CAGG:C	donor_loss	1.0000
3:138023821:AGGTA:A	donor_loss	1.0000
3:138023822:GG:G	donor_loss	1.0000
3:138023823:GTAA:G	donor_loss	1.0000
3:138023824:T:G	donor_loss	1.0000
3:138024598:T:TA	acceptor_gain	1.0000
3:138024601:CCACA:C	acceptor_loss	1.0000
3:138024602:CACAG:C	acceptor_loss	1.0000
3:138024604:CAGGT:C	acceptor_loss	1.0000
3:138024605:A:T	acceptor_loss	1.0000
3:138024606:GGT:G	acceptor_gain	1.0000
3:138024606:GGTC:G	acceptor_gain	1.0000
3:138024606:GGTCT:G	acceptor_gain	1.0000
3:138029908:G:GG	donor_gain	1.0000
3:138030968:A:AG	acceptor_gain	1.0000
3:138030969:G:GA	acceptor_gain	1.0000
3:138030969:GCT:G	acceptor_gain	1.0000
3:138030969:GCTAC:G	acceptor_gain	1.0000
3:138010442:CCAGG:C	donor_loss	0.9900
3:138010443:CAGGT:C	donor_loss	0.9900
3:138010444:AGG:A	donor_loss	0.9900
3:138010445:GG:G	donor_loss	0.9900
3:138010447:T:G	donor_loss	0.9900
3:138023457:GAATT:G	donor_gain	0.9900
3:138023641:T:A	acceptor_gain	0.9900

AlphaMissense

1700 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:138010313:T:A	W30R	0.999
3:138010313:T:C	W30R	0.999
3:138010315:G:C	W30C	0.999
3:138010315:G:T	W30C	0.999
3:138010367:G:A	G48R	0.999
3:138010367:G:C	G48R	0.999
3:138010373:T:A	W50R	0.999
3:138010373:T:C	W50R	0.999
3:138010375:G:C	W50C	0.999
3:138010375:G:T	W50C	0.999
3:138024660:T:C	F147L	0.999
3:138024662:C:A	F147L	0.999
3:138024662:C:G	F147L	0.999
3:138029808:G:T	G172V	0.999
3:138029828:T:A	W179R	0.999
3:138029828:T:C	W179R	0.999
3:138010274:G:A	G17R	0.998
3:138010274:G:C	G17R	0.998
3:138010368:G:A	G48E	0.998
3:138010371:T:A	L49H	0.998
3:138010412:T:A	C63S	0.998
3:138010413:G:C	C63S	0.998
3:138023801:G:T	G122W	0.998
3:138023802:G:A	G122E	0.998
3:138024612:T:C	C131R	0.998
3:138024624:G:A	G135R	0.998
3:138024624:G:C	G135R	0.998
3:138024625:G:A	G135E	0.998
3:138024636:T:C	F139L	0.998
3:138024638:T:A	F139L	0.998

dbSNP variants (sampled 300 via entrez): RS1000038371 (3:138016307 A>G), RS1000069390 (3:138015972 T>C), RS1000105637 (3:138016725 C>A,G), RS1000174808 (3:138018336 T>A,C), RS1000184235 (3:138029300 C>T), RS1000271949 (3:138022455 G>T), RS1000551505 (3:138027589 T>A), RS1000597934 (3:138020854 C>T), RS1000619784 (3:138029024 C>T), RS1000915858 (3:138008690 C>T), RS1000922776 (3:138027922 G>A), RS1001170870 (3:138015684 A>T), RS1001213378 (3:138022342 G>T), RS1001323133 (3:138015894 A>G), RS1001341865 (3:138028655 C>A)

Disease associations

OMIM: gene MIM:609210 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): megacolon (MONDO:0001273)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002817_1	Alzheimer’s disease in APOE e4- carriers	5.000000e-07
GCST009391_45	Metabolite levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010114	citrate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712859 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Claudins

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, increases expression	2
apocarotenal	increases expression	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
tetrathiomolybdate	decreases expression	1
ferrous chloride	increases expression	1
mercuric bromide	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	decreases expression	1
Antirheumatic Agents	increases expression	1
beta Carotene	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

21 cell lines: 10 cancer cell line, 7 transformed cell line, 4 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8DU	Abcam HCT 116 CLDN18 KO	Cancer cell line	Male
CVCL_B9G2	Abcam A-549 CLDN18 KO	Cancer cell line	Male
CVCL_D2EH	Abcam MCF-7 CLDN18 KO	Cancer cell line	Female
CVCL_E2SZ	Genomeditech CHO-K1 H_CLDN18(isoform2)	Spontaneously immortalized cell line	Female
CVCL_E5J1	CHO-K1/CLDN18.2	Spontaneously immortalized cell line	Female
CVCL_E5J2	HEK293/CLDN18.2	Transformed cell line	Female
CVCL_E6T1	Genomeditech CT26 H_CLDN18(isoform 2)-eGFP	Cancer cell line	Female
CVCL_E6TM	Genomeditech HEK-293 H_CLDN18(isoform 1)-eGFP	Transformed cell line	Female
CVCL_E6TN	Genomeditech HEK-293 H_CLDN18(isoform 2)-eGFP	Transformed cell line	Female
CVCL_E6WF	Genomeditech MC-38 H_CLDN18(isoform 2)	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery