CLDN4

Summary

CLDN4 (claudin 4, HGNC:2046) is a protein-coding gene on chromosome 7q11.23, encoding Claudin-4 (O14493). Can associate with other claudins to regulate tight junction structural and functional strand dynamics.

The protein encoded by this intronless gene belongs to the claudin family. Claudins are integral membrane proteins that are components of the epithelial cell tight junctions, which regulate movement of solutes and ions through the paracellular space. This protein is a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) and may play a role in internal organ development and function during pre- and postnatal life. This gene is deleted in Williams-Beuren syndrome, a neurodevelopmental disorder affecting multiple systems.

Source: NCBI Gene 1364 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 29 total — 1 pathogenic
• MANE Select transcript: NM_001305

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2046
Approved symbol	CLDN4
Name	claudin 4
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	CPE-R, WBSCR8, hCPE-R
Ensembl gene	ENSG00000189143
Ensembl biotype	protein_coding
OMIM	602909
Entrez	1364

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000340958, ENST00000431918, ENST00000435050, ENST00000466411, ENST00000476494

RefSeq mRNA: 1 — MANE Select: NM_001305 NM_001305

CCDS: CCDS5560

Canonical transcript exons

ENST00000340958 — 1 exons

Exon	Start	End
ENSE00001371777	73830996	73832690

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 99.36.

FANTOM5 (CAGE): breadth broad, TPM avg 50.2292 / max 1043.2680, expressed in 663 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79028	49.9824	658
79027	0.1018	59
79026	0.0740	34
79023	0.0710	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.36	gold quality
right uterine tube	UBERON:0001302	98.28	gold quality
endometrium epithelium	UBERON:0004811	98.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.19	gold quality
lower esophagus mucosa	UBERON:0035834	97.62	gold quality
skin of abdomen	UBERON:0001416	97.58	gold quality
skin of leg	UBERON:0001511	97.38	gold quality
minor salivary gland	UBERON:0001830	97.34	gold quality
rectum	UBERON:0001052	97.27	gold quality
left lobe of thyroid gland	UBERON:0001120	96.95	gold quality
esophagus mucosa	UBERON:0002469	96.92	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.75	gold quality
right lobe of thyroid gland	UBERON:0001119	96.53	gold quality
body of pancreas	UBERON:0001150	96.35	gold quality
saliva-secreting gland	UBERON:0001044	96.17	gold quality
colonic mucosa	UBERON:0000317	96.11	gold quality
thyroid gland	UBERON:0002046	96.11	gold quality
metanephros cortex	UBERON:0010533	95.87	gold quality
mouth mucosa	UBERON:0003729	95.85	gold quality
nasal cavity epithelium	UBERON:0005384	95.18	gold quality
islet of Langerhans	UBERON:0000006	94.86	gold quality
zone of skin	UBERON:0000014	94.63	gold quality
gall bladder	UBERON:0002110	94.43	gold quality
pancreas	UBERON:0001264	94.31	gold quality
mucosa of urinary bladder	UBERON:0001259	94.04	gold quality
cervix epithelium	UBERON:0004801	93.56	gold quality
upper lobe of left lung	UBERON:0008952	93.36	gold quality
cervix squamous epithelium	UBERON:0006922	92.92	silver quality
upper lobe of lung	UBERON:0008948	92.81	gold quality
transverse colon	UBERON:0001157	92.46	gold quality

Single-cell (SCXA)

Detected in 28 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	10858.75
E-MTAB-9841	yes	8529.45
E-MTAB-8221	yes	4379.17
E-GEOD-114530	yes	3994.78
E-GEOD-124472	yes	3907.15
E-MTAB-10287	yes	3711.28
E-MTAB-10885	yes	3248.31
E-CURD-114	yes	2150.08
E-HCAD-10	yes	2002.85
E-MTAB-6701	yes	1483.62
E-GEOD-130473	yes	1430.23
E-HCAD-23	yes	940.72
E-MTAB-10662	yes	806.94
E-MTAB-8530	yes	697.74
E-MTAB-8142	yes	541.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, FOXC1, GRHL2, HNF4A, NFE2L2, SP1, STAT2, TFAP4, TWIST1, ZEB2

miRNA regulators (miRDB)

41 targeting CLDN4, 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-5692A	100.00	74.40	6850
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-649	97.96	67.21	704
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1914-5P	97.83	66.21	807

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• CLDN4, clustered with CLDN3 at human chromosome 7q11, is a four-transmembrane protein with WWCC motif, defined by W-X(17-22)-W-X(2)-C-X(8-10)-C. (PMID:12736707)
• Claudin-4 is a potent inhibitor of the invasiveness and metastatic phenotype of pancreatic cancer cells, and a target of the transforming growth factor beta and Ras/Raf/extracellular signal-regulated kinase pathways. (PMID:14559813)
• The tail of claudin-2 could stabilize claudin-4, with a concomitant increase in both protein level and physiologic influence. (PMID:15366421)
• claudin 4 may play a role in the disruption of cell-to-cell adhesion in diffuse type gastric cancer and in a loss of differentiation. (PMID:15643498)
• loss of CLDN4 expression in areas of apocrine metaplasia and in the majority of grade 1 invasive carcinomas suggests a particular role for this protein in mammary glandular cell differentiation and carcinogenesis (PMID:15743508)
• tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability (PMID:16236711)
• The expression of claudin-1, -3 and -4 was upregulated 5.7-, 1.5- and 2.4-fold, respectively, in colorectal tumor tissues in comparison to the normal ones. (PMID:16253248)
• claudin 3 and claudin 4 may play a role in transformation of ovarian surface epithelium towards the malignant phenotype (PMID:16287068)
• Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool. (PMID:16439986)
• Sp1 epigenetic modifications have a critical role in regulation of the CLDN4 promoter in ovarian cancer cells (PMID:16714763)
• WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 (PMID:16949040)
• expression of claudin-4 is lower in diffuse-type gastric cancer than in intestinal-type gastric cancer (PMID:16969486)
• Overexpression of claudin-4 is associated with uterine serous papillary carcinoma (PMID:17326053)
• Tight junction proteins contribute to the permeability barrier in epidermal keratinocytes (PMID:17359339)
• When compared, small-cell-lung cancers and carcinoid tumors, adenocarcinomas, and squamous cell carcinomas in CLDN4 expression. (PMID:17418912)
• Loss of claudin expression may enhance the grade of malignancy of gastric cancer in vivo. (PMID:17459057)
• Claudin-3 and claudin-4 receptors are highly overexpressed in carcinosarcoma (PMID:17545541)
• Our data suggest that JUND and CLDN4 are critical mediators of the antiproliferative and antiviral effects of type I IFNs and further confirm the functional importance of the DNA-binding domain of Stat2. (PMID:17651017)
• The modulation of claudin-4 activity by PKCepsilon may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells. (PMID:17678893)
• vinculin plays a role in growth regulation of neuroendocrine tumors and in expression of CLD4 (PMID:17709988)
• Reduced claudin-4 expression correlates with loss of differentiation in thyroid neoplasms. (PMID:17962811)
• Cdx2 plays an important role in the regulation of intestinal claudin expression not only in gastric mucosa with intestinal metaplasia but also gastric carcinoma. (PMID:18251778)
• MMP-2, MMP-9 and claudin-4 expression may be phenotypic features, distinguishing intestinal-type and diffuse-type gastric cancer. (PMID:18283635)
• Increased expression of claudin-3 and claudin-4 may contribute to aggressive phenotype of endometrial cancer of serous papillary or clear-cell histology. Possible targets for therapeutic intervention. (PMID:18313739)
• Down-regulated expression of claudin-3 and claudin-4 in ectopic endometrium suggests that claudin-3 and claudin-4 might play a pathogenic role in the formation of endometriosis. (PMID:18384777)
• Early gastric carcinomas demonstrating I-CLDN(+) phenotype have a high risk of synchronous and metachronous secondary gastric epithelial neoplasias. (PMID:18477216)
• Claudins 1 and 4 expression was significantly associated with stage in patients with urothelial carcinoma of the upper urinary tract. (PMID:18550469)
• Claudin-4, coding for an integral membrane cell-junction protein, was the most significantly (P<0.00001) upregulated marker in both primary and metastatic tumour specimens compared with benign prostatic hyperplasia at both RNA and protein levels (PMID:18648369)
• High CLDN4 is associated with basal-like breast carcinomas. (PMID:18752049)
• We found that claudin-4 contains a sequence which is phosphorylated by atypical PKC (aPKC). These findings suggest that aPKC regulates tight junction formation through the phosphorylation of claudin-4. (PMID:18786529)
• Claudin 4 is downregulated in lobular carcinoma in situ compated with normal breast epithelium and stroma. (PMID:18954444)
• Down-regulated expression of claudin-4 might play a pathogenic role in the formation of endometriosis. (PMID:19035134)
• The expression of claudins-2, -3 and -4 in 16 rectal well-differentiated endocrine neoplasms was studied (PMID:19082451)
• Down-regulation of claudin-4 might lead to altered tight junction structure and be related to the impaired epithelial function in active ulcerative colitis. (PMID:19120888)
• Increased claudin-4 expression is associated with breast cancer. (PMID:19142967)
• The expressions of PSCA and Claudin-4 are upregulated in the pancreatic carcinomas. (PMID:19180924)
• Tight junction proteins claudin-1, claudin-3, claudin-4, and the adherens junction protein beta-catenin are overexpressed in colorectal carcinoma. (PMID:19184060)
• claudin-4, in addition to 1 and 5, might be a useful differential diagnostic marker of lung cancer in Korean people. (PMID:19231096)
• CLDN4 has a role in the optimization of the endometrium for embryo implantation. (PMID:19374770)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cldn13	ENSMUSG00000008843
rattus_norvegicus	Cldn4	ENSRNOG00000001476

Paralogs (22): CLDN11 (ENSG00000013297), CLDN18 (ENSG00000066405), 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), CLDN9 (ENSG00000213937), CLDN25 (ENSG00000228607), CLDN34 (ENSG00000234469), CLDN23 (ENSG00000253958)

Protein

Protein identifiers

Claudin-4 — O14493 (reviewed: O14493)

Alternative names: Clostridium perfringens enterotoxin receptor, Williams-Beuren syndrome chromosomal region 8 protein

All UniProt accessions (2): O14493, Q75L80

UniProt curated annotations — full annotation on UniProt →

Function. Can associate with other claudins to regulate tight junction structural and functional strand dynamics. May coassemble with CLDN8 into tight junction strands containing anion-selective channels that convey paracellular chloride permeability in renal collecting ducts. May integrate into CLDN3 strands to modulate localized tight junction barrier properties. May disrupt strand assembly of channel-forming CLDN2 and CLDN15 and inhibit cation conductance. Cannot form tight junction strands on its own.

Subunit / interactions. Can form heteropolymeric strands with other claudins. Interacts with CLDN8. Interacts with CLDN1. Directly interacts with TJP1/ZO-1. Interacts with TJP2/ZO-2 and TJP3/ZO-3. Interacts with EPHA2; phosphorylates CLDN4 and may regulate tight junctions. (Microbial infection) Interacts (via both extracellular domains) with Clostridium perfringens enterotoxin CPE; the interaction may disrupt claudin assembly in tight junctions.

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

Post-translational modifications. Phosphorylated. Phosphorylation by EPHA2 is stimulated by EFNA1 and alters interaction with TJP1.

Disease relevance. CLDN4 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.

Similarity. Belongs to the claudin family.

RefSeq proteins (1): NP_001296* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003550	Claudin4	Family
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

Catalyzed reactions (Rhea), 4 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• iodide(out) = iodide(in) (RHEA:66324)
• bromide(in) = bromide(out) (RHEA:75383)
• fluoride(in) = fluoride(out) (RHEA:76159)

UniProt features (33 total): strand 9, mutagenesis site 6, topological domain 5, transmembrane region 4, helix 4, region of interest 2, chain 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9CMI	ELECTRON MICROSCOPY	2.83
8U4V	ELECTRON MICROSCOPY	2.99
7KP4	X-RAY DIFFRACTION	3.37
5B2G	X-RAY DIFFRACTION	3.5
9CMH	ELECTRON MICROSCOPY	4
7TDN	ELECTRON MICROSCOPY	5
8U5B	ELECTRON MICROSCOPY	5.3
7TDM	ELECTRON MICROSCOPY	6.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14493-F1	84.50	0.54

Antibody-complex structures (SAbDab): 5 — 7TDM, 7TDN, 8U4V, 8U5B, 9CMI

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): 208

Disulfide bonds (1): 54–64

Mutagenesis-validated functional residues (6):

Position	Phenotype
35	decreases interaction with clostridium perfringens cpe.
35	abolishes interaction with clostridium perfringens cpe.
40	no effect on interaction with clostridium perfringens cpe.
40	strongly decreases interaction with clostridium perfringens cpe.
53	decreases interaction with clostridium perfringens cpe.
208	loss of phosphorylation by epha2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 240 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_CIRCADIAN_RHYTHM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_WOUND_HEALING, ENK_UV_RESPONSE_KERATINOCYTE_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, MODULE_64, IVANOVA_HEMATOPOIESIS_MATURE_CELL, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_INORGANIC_ANION_TRANSPORT, KEGG_TIGHT_JUNCTION, TGACCTY_ERR1_Q2, NAGASHIMA_NRG1_SIGNALING_UP, RODRIGUES_NTN1_TARGETS_DN

GO Biological Process (16): cell adhesion (GO:0007155), female pregnancy (GO:0007565), circadian rhythm (GO:0007623), calcium-independent cell-cell adhesion (GO:0016338), regulation of cell morphogenesis (GO:0022604), positive regulation of cell migration (GO:0030335), response to progesterone (GO:0032570), establishment of skin barrier (GO:0061436), renal absorption (GO:0070293), bicellular tight junction assembly (GO:0070830), positive regulation of wound healing (GO:0090303), paracellular transport (GO:0160184), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), structural molecule activity (GO:0005198), chloride channel activity (GO:0005254), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), basal plasma membrane (GO:0009925), apical plasma membrane (GO:0016324), apicolateral plasma membrane (GO:0016327), lateral plasma membrane (GO:0016328), chloride channel complex (GO:0034707), 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
plasma membrane region	3
transport	2
cellular anatomical structure	2
cellular process	1
multi-organism reproductive process	1
multi-multicellular organism process	1
rhythmic process	1
cell-cell adhesion	1
cell morphogenesis	1
regulation of anatomical structure morphogenesis	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
response to steroid hormone	1
response to ketone	1
skin epidermis development	1
renal system process	1
apical junction assembly	1
tight junction assembly	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
signaling receptor activity	1
molecular_function	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
protein binding	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
apical junction complex	1
tight junction	1
basal part of cell	1

Protein interactions and networks

STRING

1598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN4	TJP1	Q07157	996
CLDN4	OCLN	Q16625	988
CLDN4	CLDN12	P56749	958
CLDN4	F11R	Q9Y624	919
CLDN4	TJP2	Q9UDY2	890
CLDN4	EPHA2	P29317	839
CLDN4	CLDN1	O95832	838
CLDN4	CLDN7	O95471	807
CLDN4	EFNB1	P98172	801
CLDN4	MARVELD2	Q8N4S9	783
CLDN4	CDH1	P12830	781
CLDN4	TJP3	O95049	774
CLDN4	EPCAM	P16422	718
CLDN4	CLDN8	P56748	711
CLDN4	CTNNB1	P35222	666

IntAct

156 interactions, top by confidence:

A	B	Type	Score
CLDN4	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	TRIM59	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	MFSD14B	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	GOLM1	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	TSPO2	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	TMEM52B	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	ICAM3	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	FFAR2	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	SYT2	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	GJA8	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	AQP6	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	CLEC14A	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
CLDN4	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN4	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (72): CLDN4 (Affinity Capture-MS), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid), CLDN4 (Two-hybrid)

ESM2 similar proteins: A0A8C0N7E5, C3VMW3, D3ZQJ0, O00501, O14493, O15551, O19005, O35054, O35912, O54942, O88551, O95471, O95484, O95832, P56745, P56746, P56747, P56748, P56750, P78369, Q2HJ22, Q2KIY2, Q3B7N4, Q5E9L0, Q5QT56, Q5R8E5, Q63400, Q6BBL6, Q6DHB5, Q6DHP1, Q6L708, Q765N9, Q8BXA6, Q8N6F1, Q95KM5, Q9D1D1, Q9ET38, Q9JKD6, Q9QYW5, Q9YH90

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

3 interactions.

A	Effect	B	Mechanism
SNAI1	“down-regulates quantity by repression”	CLDN4	“transcriptional regulation”
CLDN4	down-regulates	Epithelial-mesenchymal_transition
EPHA2	“down-regulates activity”	CLDN4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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	52.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	47.0×	7e-13
Dopamine Neurotransmitter Release Cycle	5	46.0×	2e-06
Long-term potentiation	5	44.1×	2e-06
Neurexins and neuroligins	12	43.8×	5e-15
Protein-protein interactions at synapses	8	39.4×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	64.6×	4e-12
protein localization to synapse	6	56.7×	1e-07
receptor clustering	7	53.9×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	36.7×	1e-06
cell-cell adhesion	9	11.3×	6e-06
protein-containing complex assembly	8	11.2×	3e-05
chemical synaptic transmission	7	6.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
978415	NC_000007.14:g.73773313_74086695del	Pathogenic

SpliceAI

334 predictions. Top by Δscore:

Variant	Effect	Δscore
7:73827820:GC:G	donor_gain	0.9700
7:73827822:G:GG	donor_gain	0.9700
7:73827949:G:T	donor_gain	0.9600
7:73828062:G:GT	donor_gain	0.9600
7:73827827:C:G	donor_gain	0.9400
7:73828049:A:T	donor_gain	0.9400
7:73827776:G:GT	donor_gain	0.8800
7:73827949:G:GT	donor_gain	0.8800
7:73831165:A:T	acceptor_gain	0.8600
7:73828048:G:GT	donor_gain	0.8400
7:73830991:G:GC	acceptor_gain	0.8400
7:73831085:C:CA	acceptor_gain	0.8200
7:73831164:CAG:C	acceptor_gain	0.8000
7:73830432:C:G	acceptor_gain	0.7900
7:73828058:G:T	donor_gain	0.7800
7:73827976:G:GA	donor_gain	0.7600
7:73827977:GACT:G	donor_gain	0.7600
7:73828598:A:AG	acceptor_gain	0.7600
7:73828599:G:GG	acceptor_gain	0.7600
7:73827975:T:TA	donor_gain	0.7500
7:73830993:G:C	acceptor_gain	0.7500
7:73828358:A:T	donor_gain	0.7400
7:73827880:C:G	donor_gain	0.7300
7:73828062:G:T	donor_gain	0.7200
7:73828594:TTTTA:T	acceptor_loss	0.7200
7:73828595:TTTA:T	acceptor_loss	0.7200
7:73828596:TTAGA:T	acceptor_loss	0.7200
7:73828597:TA:T	acceptor_loss	0.7200
7:73828598:AGAT:A	acceptor_gain	0.7200
7:73828599:GATG:G	acceptor_gain	0.7200

AlphaMissense

1340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:73831346:G:C	G49R	0.998
7:73831640:T:C	F147L	0.998
7:73831642:C:A	F147L	0.998
7:73831642:C:G	F147L	0.998
7:73831391:T:A	C64S	0.997
7:73831392:G:C	C64S	0.997
7:73831703:T:A	W168R	0.997
7:73831703:T:C	W168R	0.997
7:73831289:T:A	W30R	0.996
7:73831289:T:C	W30R	0.996
7:73831291:G:C	W30C	0.996
7:73831291:G:T	W30C	0.996
7:73831352:T:A	W51R	0.996
7:73831352:T:C	W51R	0.996
7:73831354:G:C	W51C	0.996
7:73831354:G:T	W51C	0.996
7:73831682:G:C	G161R	0.996
7:73831250:G:C	G17R	0.995
7:73831346:G:T	G49C	0.995
7:73831481:G:C	G94R	0.995
7:73831304:T:C	F35L	0.994
7:73831306:C:A	F35L	0.994
7:73831306:C:G	F35L	0.994
7:73831361:T:A	C54S	0.994
7:73831361:T:C	C54R	0.994
7:73831362:G:C	C54S	0.994
7:73831391:T:C	C64R	0.994
7:73831443:G:C	R81P	0.994
7:73831460:A:C	S87R	0.994
7:73831462:C:A	S87R	0.994

dbSNP variants (sampled 300 via entrez): RS1000673893 (7:73832006 G>A,C,T), RS1002436808 (7:73829373 G>A,C), RS1002774389 (7:73830699 T>C), RS1003089438 (7:73830453 C>A), RS1005192896 (7:73830206 C>A), RS1006751777 (7:73832266 C>T), RS1008871803 (7:73829469 T>G), RS1009379301 (7:73829738 C>G,T), RS1010979897 (7:73829188 C>T), RS1011118664 (7:73829407 G>A,C), RS1011318555 (7:73830488 G>A), RS1011455118 (7:73830807 G>A), RS1013332095 (7:73832867 G>A,T), RS1014372995 (7:73829106 T>C), RS1014874016 (7:73830239 G>A)

Disease associations

OMIM: gene MIM:602909 | disease phenotypes: MIM:194050

GenCC curated gene-disease

Mondo (1): Williams syndrome (MONDO:0008678)

Orphanet (1): Williams syndrome (Orphanet:904)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018980	Williams Syndrome	C10.597.606.360.970; C14.280.484.048.750.535.960; C16.131.260.970; C16.320.180.970

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	7
Valproic Acid	affects cotreatment, increases expression	5
deoxynivalenol	affects localization, decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Estradiol	affects cotreatment, decreases expression	3
Tobacco Smoke Pollution	increases expression	3
Cadmium Chloride	increases expression	3
ochratoxin A	affects reaction, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
trans-10,cis-12-conjugated linoleic acid	increases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects expression, affects reaction, decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects localization, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
Okadaic Acid	increases expression	2
aristolochic acid I	increases expression	1
propionaldehyde	decreases expression, increases expression	1
sanguinarine	decreases expression	1
bisphenol A	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
quercitrin	affects expression	1
butyraldehyde	increases expression	1
tetrathiomolybdate	decreases expression	1
benzo(e)pyrene	increases methylation	1
diallyl disulfide	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3VA	HT-1080/hCLDN-4	Cancer cell line	Male
CVCL_D3PN	CHO/CLDN4	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT04807517	PHASE4	COMPLETED	Buspirone Treatment of Anxiety in Williams Syndrome
NCT00876200	PHASE2	COMPLETED	Efficacy of Minoxidil in Children With Williams-Beuren Syndrome
NCT06087757	PHASE2	ACTIVE_NOT_RECRUITING	Clemastine Treatment in Individuals With Williams Syndrome
NCT06315699	PHASE2	COMPLETED	Clemastine Fumarate in the Treatment of Neurodevelopmental Delays in Williams Syndrome
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00013962	Not specified	COMPLETED	Vitamin D Metabolism and the Williams Syndrome
NCT01132885	Not specified	RECRUITING	Defining the Brain Phenotype of Children With Williams Syndrome
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01864304	Not specified	COMPLETED	Fat Distribution and Glucose Metabolism in Williams Syndrome
NCT02212314	Not specified	COMPLETED	Response Inhibition Training for Children With Williams Syndrome
NCT02692846	Not specified	COMPLETED	WS-SAVE Study (Williams Syndrome Skin and Vessel Elasticity Study)
NCT02706639	Not specified	COMPLETED	Williams Syndrome (WS) and Supravalvar Aortic Stenosis (SVAS) DNA and Tissue Bank
NCT02840448	Not specified	COMPLETED	Impact of Elastin Mediated Vascular Stiffness on End Organs
NCT03758651	Not specified	COMPLETED	Williams Syndrome Strength, Hormones, Activity & Adiposity, DNA Programming, Eating Study
NCT03827525	Not specified	UNKNOWN	Cognitive and Behavioral Therapy of Anxiety in Williams Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04051086	Not specified	UNKNOWN	Quantification of Elastin Markers Synthesis in Williams-Beuren Syndrome and 7q11.23 Micro-duplication Syndrome
NCT04095585	Not specified	COMPLETED	Molecular Characterization of Patients Affected by Williams Syndrome and Autism.
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04610424	Not specified	UNKNOWN	Cooperative Parent Mediated Therapy in Children With Fragile X Syndrome and Williams Syndrome
NCT05430763	Not specified	WITHDRAWN	Motor Deficits and Signal Conduction in Individuals With Williams Syndrome
NCT06740162	Not specified	RECRUITING	Physical Activity and Community EmPOWERment Project
NCT06930417	Not specified	RECRUITING	Characterization and Natural History of Williams Syndrome and Other Chromosome 7q11.23 Variants
NCT07285720	Not specified	RECRUITING	Phonological Constraints on Language Development in Individuals With Williams Syndrome
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders
NCT07509879	Not specified	NOT_YET_RECRUITING	Research on the Molecular Mechanism of Cognitive Differences Between Williams Syndrome and Autism Spectrum Disorder
NCT07537374	Not specified	NOT_YET_RECRUITING	A Case-Control Observational Study of Peripheral Blood-Derived iPSC Models to Investigate Oligodendrocyte Lineage Development in Children With Williams Syndrome and Healthy Controls