CLDN6

Summary

CLDN6 (claudin 6, HGNC:2048) is a protein-coding gene on chromosome 16p13.3, encoding Claudin-6 (P56747). Plays a major role in tight junction-specific obliteration of the intercellular space. It is a selective cancer dependency (DepMap: 10.0% of cell lines).

Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. This gene encodes a component of tight junction strands, which is a member of the claudin family. The protein is an integral membrane protein and is one of the entry cofactors for hepatitis C virus. The gene methylation may be involved in esophageal tumorigenesis. This gene is adjacent to another family member CLDN9 on chromosome 16.

Source: NCBI Gene 9074 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 45 total
• GTEx eGene: eQTL in 4 tissues, sQTL in 0 (q < 0.05)
• Cancer dependency (DepMap): dependent in 10.0% of screened cell lines
• Constraint (gnomAD): pLI 0.24 (intermediate), LOEUF 1.76 (unconstrained)
• MANE Select transcript: NM_021195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2048
Approved symbol	CLDN6
Name	claudin 6
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184697
Ensembl biotype	protein_coding
OMIM	615798
Entrez	9074

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

MANE Select: ENST00000328796

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1, TSL 5: 1

ENST00000328796, ENST00000396925, ENST00000572154, ENST00000939715, ENST00000939716, ENST00000939717, ENST00000939718, ENST00000939719, ENST00001140756

RefSeq mRNA: 1 — MANE Select: NM_021195 NM_021195

CCDS: CCDS10488

Canonical transcript exons

ENST00000328796 — 2 exons

Exon	Start	End
ENSE00001297087	3014712	3016042
ENSE00001432497	3018149	3018183

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 83.86.

FANTOM5 (CAGE): breadth broad, TPM avg 29.6392 / max 2127.8243, expressed in 380 samples.

Highest expression (Bgee): primordial germ cell in gonad, buccal mucosa cell, cortical plate, islet of Langerhans, epithelial cell of pancreas.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CLDN6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

4 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Frontal Cortex BA9	eqtl	6.4e-03	+0.33	16:3028615:CATT:C
Brain Anterior cingulate cortex BA24	eqtl	1.2e-02	+2.11	16:2300655:AG:A
Thyroid	eqtl	3.0e-02	+0.18	16:3002757:G:C
Brain Cerebellum	eqtl	4.2e-02	+1.17	16:3019818:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
155977	29.2504	259
155979	0.3888	132

Top tissues by expression

showing 100 of 235 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.86	gold quality
buccal mucosa cell	CL:0002336	71.49	silver quality
cortical plate	UBERON:0005343	70.43	gold quality
islet of Langerhans	UBERON:0000006	68.24	gold quality
epithelial cell of pancreas	CL:0000083	67.03	gold quality
kidney epithelium	UBERON:0004819	66.70	gold quality
upper arm skin	UBERON:0004263	65.53	gold quality
epithelium of nasopharynx	UBERON:0001951	62.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.58	gold quality
vena cava	UBERON:0004087	61.58	gold quality
saphenous vein	UBERON:0007318	60.45	gold quality
nasal cavity epithelium	UBERON:0005384	59.84	gold quality
inferior vagus X ganglion	UBERON:0005363	59.34	gold quality
gingival epithelium	UBERON:0001949	59.00	gold quality
layer of synovial tissue	UBERON:0007616	58.56	gold quality
dorsal plus ventral thalamus	UBERON:0001897	58.38	gold quality
subthalamic nucleus	UBERON:0001906	58.32	gold quality
pericardium	UBERON:0002407	58.00	gold quality
trigeminal ganglion	UBERON:0001675	57.97	gold quality
ventral tegmental area	UBERON:0002691	57.96	gold quality
putamen	UBERON:0001874	57.93	gold quality
medulla oblongata	UBERON:0001896	57.90	gold quality
dorsal root ganglion	UBERON:0000044	57.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	57.70	gold quality
nipple	UBERON:0002030	57.47	gold quality
superior surface of tongue	UBERON:0007371	57.47	gold quality
pylorus	UBERON:0001166	57.43	gold quality
pons	UBERON:0000988	57.35	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	57.34	gold quality
synovial joint	UBERON:0002217	57.31	gold quality
superior vestibular nucleus	UBERON:0007227	57.26	gold quality
thymus	UBERON:0002370	57.23	gold quality
substantia nigra pars compacta	UBERON:0001965	57.18	gold quality
cardia of stomach	UBERON:0001162	57.15	gold quality
renal medulla	UBERON:0000362	57.12	gold quality
cerebellar vermis	UBERON:0004720	57.04	gold quality
tongue	UBERON:0001723	57.01	gold quality
trachea	UBERON:0003126	56.99	gold quality
pancreas	UBERON:0001264	56.91	gold quality
lateral globus pallidus	UBERON:0002476	56.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	56.84	gold quality
penis	UBERON:0000989	56.83	gold quality
placenta	UBERON:0001987	56.79	gold quality
pharyngeal mucosa	UBERON:0000355	56.77	gold quality
body of tongue	UBERON:0011876	56.72	gold quality
urethra	UBERON:0000057	56.54	gold quality
quadriceps femoris	UBERON:0001377	56.21	gold quality
amniotic fluid	UBERON:0000173	56.17	gold quality
cerebellar hemisphere	UBERON:0002245	55.95	gold quality
cerebellar cortex	UBERON:0002129	55.89	gold quality
oocyte	CL:0000023	55.70	gold quality
cerebellum	UBERON:0002037	55.43	gold quality
vastus lateralis	UBERON:0001379	55.14	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.98	gold quality
skeletal muscle tissue	UBERON:0001134	54.96	silver quality
right hemisphere of cerebellum	UBERON:0014890	54.57	gold quality
deltoid	UBERON:0001476	54.29	gold quality
heart right ventricle	UBERON:0002080	54.24	gold quality
stromal cell of endometrium	CL:0002255	54.23	silver quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
metanephros	UBERON:0000081	53.71	silver quality
gingiva	UBERON:0001828	53.69	gold quality
tibialis anterior	UBERON:0001385	53.63	silver quality
muscle tissue	UBERON:0002385	53.36	silver quality
epithelium of mammary gland	UBERON:0003244	52.89	gold quality
caudate nucleus	UBERON:0001873	52.88	gold quality
mammary duct	UBERON:0001765	52.73	gold quality
lower lobe of lung	UBERON:0008949	52.70	silver quality
body of pancreas	UBERON:0001150	52.19	gold quality
trabecular bone tissue	UBERON:0002483	52.15	gold quality
parietal lobe	UBERON:0001872	51.56	gold quality
myocardium	UBERON:0002349	51.39	gold quality
nucleus accumbens	UBERON:0001882	51.28	gold quality
postcentral gyrus	UBERON:0002581	50.32	gold quality
Brodmann (1909) area 46	UBERON:0006483	50.29	gold quality
prefrontal cortex	UBERON:0000451	50.27	gold quality
testis	UBERON:0000473	50.08	gold quality
pancreatic ductal cell	CL:0002079	49.98	silver quality
ileal mucosa	UBERON:0000331	49.63	silver quality
pigmented layer of retina	UBERON:0001782	49.52	gold quality
bone marrow	UBERON:0002371	49.36	silver quality
left testis	UBERON:0004533	48.91	gold quality
brain	UBERON:0000955	48.15	gold quality
right testis	UBERON:0004534	48.14	gold quality
jejunum	UBERON:0002115	48.03	gold quality
entorhinal cortex	UBERON:0002728	47.78	gold quality
kidney	UBERON:0002113	47.67	gold quality
occipital lobe	UBERON:0002021	47.34	gold quality
globus pallidus	UBERON:0001875	47.30	gold quality
frontal cortex	UBERON:0001870	47.14	gold quality
forebrain	UBERON:0001890	47.09	gold quality
midbrain	UBERON:0001891	47.09	gold quality
cortex of kidney	UBERON:0001225	46.44	silver quality
right uterine tube	UBERON:0001302	46.33	gold quality
biceps brachii	UBERON:0001507	46.31	gold quality
neocortex	UBERON:0001950	46.28	gold quality
blood	UBERON:0000178	46.01	silver quality
substantia nigra	UBERON:0002038	45.73	gold quality
hypothalamus	UBERON:0001898	45.52	gold quality
nasal cavity mucosa	UBERON:0001826	45.35	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	1088.16
E-MTAB-9388	yes	832.43
E-MTAB-6701	yes	741.03
E-MTAB-10485	yes	579.28
E-MTAB-10662	yes	392.76
E-MTAB-8221	yes	390.74
E-GEOD-124472	yes	375.55
E-MTAB-8205	yes	316.74
E-MTAB-8271	yes	121.52
E-HCAD-10	yes	26.08
E-ANND-3	no	1.83

HPA expression

RNA tissue specificity: Tissue enhanced

47 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Choroid plexus	tissue	4.0
Nucleus accumbens	tissue	3.6
Hippocampus	tissue	3.4
Locus coeruleus	tissue	2.8
Postcentral gyrus	tissue	2.4
Testis	tissue	0.8
Pancreas	tissue	0.7
Placenta	tissue	0.7
Pituitary gland	tissue	0.3
Spinal cord	tissue	0.3
Cerebral cortex	tissue	0.2
Amygdala	tissue	0.2
Hypothalamus	tissue	0.2
Lung	tissue	0.2
Adrenal gland	tissue	0.2
Hippocampal formation	tissue	0.2
Insular cortex	tissue	0.2
Prefrontal cortex	tissue	0.1
Stomach 1	tissue	0.1
Retina	tissue	0.1
Pons	tissue	0.1
Skeletal muscle	tissue	0.1
Endometrium 1	tissue	0.1
Motor cortex	tissue	0.1
Basal ganglia	tissue	0.1
Putamen	tissue	0.1
Midbrain	tissue	0.1
Medulla oblongata	tissue	0.1
Thalamus	tissue	0.1
Superior colliculi	tissue	0.1
Cerebellum	tissue	0.1
Substantia nigra	tissue	0.1
Small intestine	tissue	0.1
Gallbladder	tissue	0.1
Duodenum	tissue	0.1
Thymus	tissue	0.1
Bone marrow	tissue	0.1
Entorhinal cortex	tissue	0.1
Ventral forebrain	tissue	0.1
Retrosplenial and cingulate cortex	tissue	0.1
Periaqueductal gray	tissue	0.1
Olfactory bulb	tissue	0.1
Septum	tissue	0.1
Somatosensory cortex	tissue	0.1
Retrosplenial cortex	tissue	0.1
Temporal cortex	tissue	0.1
Occipital cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — Flocculonodular lobe (4.9), Vermis (4.9), Cerebellar cortex (3.9), Corticomedial amygdala (3.9), Olfactory area (3.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A

miRNA regulators (miRDB)

Targeting CLDN6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

19 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-9903	98.47	66.70	748
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-1910-5P	97.42	66.36	844
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-3943	95.87	64.57	523

Functional genomics

gnomAD constraint: pLI 0.239, LOEUF 1.76, missense Z 0.0859 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000328796 — one region, missense o/e 0.98. DepMap (CRISPR cell-line fitness): dependent in 10.0% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KMS-11 (-1.042), CAMA-1 (-0.99), HT-144_DAB_R (-0.87), Ki-JK (-0.852), KNS-81 (-0.833), 1411H (-0.823), Du4475 (-0.819), COR-L47 (-0.817), NCI-H23 (-0.797), SU-DHL-5 (-0.795), 253J (-0.793), SCS-214 (-0.78), HT-144_DAB_ROX_R (-0.751), ES4 (-0.736), INA6 (-0.733).

Literature-anchored findings (GeneRIF, showing 40)

• CLDN6, clustered with CLDN9 at human chromosome 16p13.3, is a four-transmembrane protein with WWCC motif, defined by W-X(17-22)-W-X(2)-C-X(8-10)-C. (PMID:12736707)
• CLDN6 and CLDN9, but not CLDN1, are expressed in peripheral blood mononuclear cells, an additional site of HCV replication. (PMID:17804490)
• claudin-6 and claudin-9 expressed in CD81+ cells also enable the entry of HCV pseudoparticles derived from six of the major genotypes. (PMID:18234789)
• CLDN6 may be a useful positive marker to help further identify atypical teratoid/rhabdoid tumors for diagnostic and treatment purposes (PMID:19220299)
• Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma. (PMID:19288010)
• Claudins 6, 7, and 9 expressions are closely related to gastric carcinogenesis (PMID:19960275)
• Claudin 6 was not found in epithelioid glioblastomas or rhabdoid glioblastomas. (PMID:20118769)
• claudin-6, downregulates the malignant phenotype of breast carcinoma. (PMID:20215972)
• The up-regulation of claudin-6 expression in MCF-7 breast cancer cells suppresses their malignant phenotypes with a correlation with the restoration of tight junction integrity. (PMID:20367941)
• 17beta-E2 might regulate the expression of claudin-6 and inhibit the proliferation and migration of MCF-7 cells. (PMID:20388399)
• Increased expression of claudin-6, claudin-7, or claudin-9 is sufficient to enhance tumorigenic properties of a gastric adenocarcinoma cell line. (PMID:20874001)
• CLDN6 is not a specific biomarker for atypical teratoid rhabdoid tumors as it is expressed in a variety of other pediatric CNS and soft tissue tumors. (PMID:21989342)
• Our results show that claudin-6 protein is significantly down-regulated in breast invasive ductal carcinomas (PMID:22455563)
• ASK1 signal may play a positive role in the inhibitory effect of claudin-6 in breast cancer. (PMID:22925655)
• Only some hepatitis C virus strains efficiently use CLDN6 for infection. (PMID:23775920)
• This work provides a proof of concept for the use of Claudin-6 to eliminate residual undifferentiated human pluripotent stem cells from culture. (PMID:23778593)
• Although claudin-6 and claudin-9 can serve as entry factors in cell lines, hepatitis C virus infection into human hepatocytes is not dependent on claudin-6 and claudin-9. (PMID:23864633)
• The expression of claudin-6 was down regulated in gastric cancer tissue. (PMID:23919729)
• High levels of CLDN6 are associated with non-small-cell lung cancer. (PMID:24710653)
• The expression of ASK1 is correlated with the level of claudin-6 in cervical carcinoma cells and tissues. (PMID:26191261)
• Data show that claudin-6 (CLDN6) R209Q and occludin (OCLN) P24A mutations do not affect HCV pseudoparticles (HCVpp) entry. (PMID:26561856)
• Results show that DNA methylation down-regulates CLDN6 expression through MeCP2 binding to the CLDN6 promoter, deacetylating H3 and H4, and altering chromatin structure, consequently promoting migratory and invasive phenotype in breast cancer cells. (PMID:27461117)
• suggest that claudin-6 induces MMP-2 activation through claudin-1 membrane expression (PMID:27914788)
• Cldn6 was decreased in alveolar type II-like epithelial cells (A549) and primary small airway epithelial cells when exposed to cigarette smoke ext (PMID:27982694)
• high expression of CLDN 6 was observed in approx. 65% of the myxofibrosarcomas, whereas the benign soft tissue tumors did not show a high expression of CLDN 6. The expression of CLDN 6 in the myxofibrosarcomas was significantly higher than those of other tumor specimens. Among the myxofibrosarcomas, the high expression of CLDN 6 was correlated with high FNCLCC grades and high AJCC stages. (PMID:28476380)
• In conclusion, this information from bioinformatics analysis will help future attempts to better understand CLDN6 regulation and functions. (PMID:28656265)
• we demonstrated that the downregulation of CLDN6 is regulated through promoter methylation by DNMT1, which depends on the SMAD2 pathway, and that CLDN6 is a key regulator in the SMAD2/DNMT1/CLDN6 pathway to inhibit EMT, migration and invasion of breast cancer cells (PMID:28867761)
• these results suggest that Helicobacter pylori lipopolysaccharide induces TLR2 expression in the gastric adenocarcinoma cells, and that the longer the exposure to lipopolysaccharide, the greater the expression of TLR2 in the cell membrane; consequently the expression of claudin-4, -6, -7 and -9 also increases (PMID:29031421)
• Study provides evidence that high expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. (PMID:29116019)
• Antibodies recognizing native CLDN6 as displayed on cell surfaces and mediating complement-dependent cytotoxicity were elicited in vaccinated animals. The data suggest applications of CLDN6 displaying Virus-like particles in cancer immunotherapy. (PMID:29131519)
• CLDN6 enhances the chemoresistance to ADM via activating the AF-6/ERK signaling pathway and up-regulating cancer stem cell characters in MDAMB231 cells. (PMID:29159771)
• this is the first study to demonstrate that the inhibitory effect of ERbeta on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade. (PMID:31412908)
• Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer. (PMID:31654186)
• CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer. (PMID:31827075)
• Downregulation of CLDN6 inhibits cell proliferation, migration, and invasion via regulating EGFR/AKT/mTOR signalling pathway in hepatocellular carcinoma. (PMID:32056244)
• A SUMOylation-dependent HIF-1alpha/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis. (PMID:32093760)
• Claudin-6 is down-regulated in gastric cancer and its potential pathway. (PMID:32390606)
• Aberrant Claudin-6-Adhesion Signaling Promotes Endometrial Cancer Progression via Estrogen Receptor alpha. (PMID:33727343)
• Effects of the Tight Junction Protein CLDN6 on Cell Migration and Invasion in High-Grade Meningioma. (PMID:33862296)
• Claudin 6: Therapeutic prospects for tumours, and mechanisms of expression and regulation (Review). (PMID:34296304)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cldn6	ENSMUSG00000023906
rattus_norvegicus	Cldn6	ENSRNOG00000077752

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), CLDN24 (ENSG00000185758), CLDN4 (ENSG00000189143), CLDN9 (ENSG00000213937), CLDN25 (ENSG00000228607), CLDN34 (ENSG00000234469), CLDN23 (ENSG00000253958)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R8E5	99.6%	Diamond
Chlorocebus aethiops	O19005	99.0%	Diamond
Bos taurus	Q5E9L0	96.1%	Diamond
Canis lupus familiaris	Q95KM5	94.5%	Diamond
Sus scrofa	C3VMW3	85.8%	Diamond
Danio rerio	Q6DHP1	70.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PAQR4	protein-coding	124222
GREP1	protein-coding	283875
CLDN9	protein-coding	9080
PKMYT1	protein-coding	9088
BICDL2	protein-coding	146439
TNFRSF12A	protein-coding	51330
HCFC1R1	protein-coding	54985
THOC6	protein-coding	79228
KREMEN2	protein-coding	79412
MMP25-AS1	ncRNA	100507419
MMP25	protein-coding	64386

Protein

Protein identifiers

Claudin-6 — P56747 (reviewed: P56747)

Alternative names: Skullin

All UniProt accessions (2): I3L1E7, P56747

UniProt curated annotations — full annotation on UniProt →

Function. Plays a major role in tight junction-specific obliteration of the intercellular space. (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) entry into hepatic cells.

Subunit / interactions. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3. Interacts with CLDN1, CD81 and OCLN.

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

Tissue specificity. Expressed in the liver, in peripheral blood mononuclear cells and hepatocarcinoma cell lines.

Similarity. Belongs to the claudin family.

RefSeq proteins (1): NP_067018* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003925	Claudin6	Family
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

UniProt features (16 total): topological domain 5, modified residue 4, transmembrane region 4, chain 1, region of interest 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56747-F1	80.36	0.47

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

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 (4)

Type	Positions
Phosphoserine	201, 203, 208, 212

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-420029	Tight junction interactions	electronic

MSigDB gene sets: 127 (showing top): ATF_B, PEREZ_TP63_TARGETS, GOBP_APICAL_JUNCTION_ASSEMBLY, KEGG_TIGHT_JUNCTION, CREBP1_Q2, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST, GOBP_VIRAL_LIFE_CYCLE, JIANG_TIP30_TARGETS_DN, ATF3_Q6, CREB_Q2_01, GOCC_APICOLATERAL_PLASMA_MEMBRANE, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER, GOBP_CELL_JUNCTION_ASSEMBLY

GO Biological Process (4): cell adhesion (GO:0007155), calcium-independent cell-cell adhesion (GO:0016338), bicellular tight junction assembly (GO:0070830), symbiont entry into host cell (GO:0046718)

GO Molecular Function (5): virus receptor activity (GO:0001618), structural molecule activity (GO:0005198), identical protein binding (GO:0042802), cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), apicolateral plasma membrane (GO:0016327), membrane (GO:0016020)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

18 GO namespaces:

Category	Terms
cell-cell adhesion	2
cellular process	1
apical junction assembly	1
tight junction assembly	1
viral life cycle	1
symbiont entry into host	1
symbiont entry into host cell	1
exogenous protein binding	1
molecular_function	1
protein binding	1
cell adhesion mediator activity	1
binding	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
plasma membrane region	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
plasma membrane	CC	direct assay
virus receptor activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 700 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN6	CLDN12	P56749	631
CLDN6	OCLN	Q16625	531
CLDN6	TJP2	Q9UDY2	511
CLDN6	TJP3	O95049	459
CLDN6	TJP1	Q07157	450
CLDN6	MARVELD2	Q8N4S9	388
CLDN6	BPIFB2	Q8N4F0	357
CLDN6	CLDN16	Q9Y5I7	357
CLDN6	FREM1	Q5H8C1	355
CLDN6	EPCAM	P16422	345
CLDN6	SCARA3	Q6AZY7	345
CLDN6	ILDR1	Q86SU0	329
CLDN6	F11R	Q9Y624	327
CLDN6	YLPM1	P49750	324
CLDN6	CDH1	P12830	323

IntAct

Human interaction partners of CLDN6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
MS4A3	physical association	0.560	5
IGFBP5	physical association	0.560	3
MUC1	physical association	0.560	3
PMP22	physical association	0.560	3
SLC30A8	physical association	0.560	3
TMEM179B	physical association	0.560	3
MAPK8	physical association	0.490	3

BioGRID (20 interactions; top human partners by supporting records): TJP1 (Reconstituted Complex; 3 records), PTEN (Affinity Capture-Western; 2 records), CLIC1 (Affinity Capture-MS), ETS2 (Positive Genetic), IGFBP5 (Two-hybrid), KLF1 (Negative Genetic), MS4A3 (Two-hybrid), MUC1 (Two-hybrid), PEG10 (Positive Genetic), PMP22 (Two-hybrid), RUNX1T1 (Positive Genetic), TGFBR2 (Negative Genetic), TMEM179B (Two-hybrid), TRIM71 (Affinity Capture-RNA), U2AF2 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for CLDN6: 45 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	4
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 95):

Position(s)	Effect	Δscore	Sites
16:3016045	acceptor_gain	1.0000
16:3016049	acceptor_gain	0.9900
16:3018147–3018148	donor_loss	0.9900	5
16:3016043–3016044	acceptor_loss	0.9800	6
16:3016047–3016048	acceptor_gain	0.9800	2
16:3016056	acceptor_loss	0.9600
16:3017491	donor_gain	0.7700
16:3016038–3016039	acceptor_loss	0.7500	6
16:3016040	acceptor_loss	0.7400
16:3015161	acceptor_gain	0.6600

AlphaMissense

584 missense substitutions predicted likely pathogenic (of 1,377 scored), across 162 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M52	9	0.799	0.953
F147	8	0.945	0.998
D68	8	0.790	0.918
C54	7	0.986	0.994
W30	7	0.979	0.996
C64	7	0.979	0.994
F35	7	0.978	0.996
W51	7	0.973	0.995
E159	7	0.912	0.970
W168	7	0.912	0.995
W47	7	0.889	0.970
S58	7	0.873	0.966
W138	7	0.837	0.959
E48	7	0.777	0.936
G161	6	0.986	0.994
G49	6	0.983	0.997
K157	6	0.965	0.994
P28	6	0.958	0.987
R81	6	0.927	0.985
G60	6	0.922	0.976

HPA cancer prognostics

RNA cancer specificity: Group enriched (Ovary Serous Cystadenocarcinoma, Testicular Germ Cell Tumor, Uterine Corpus Endometrial Carcinoma)

Disease associations

OMIM: gene MIM:615798 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects cotreatment	6
trichostatin A	affects cotreatment, increases expression, decreases methylation	4
Tobacco Smoke Pollution	increases expression	3
methylmercuric chloride	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Triclosan	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
terbufos	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	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
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Azacitidine	increases expression, affects cotreatment, decreases methylation	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression, affects cotreatment	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Dimethyl Sulfoxide	decreases expression, decreases reaction, decreases methylation, increases expression	1
Dimethylnitrosamine	increases expression, decreases reaction	1

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 1 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3VC	HT-1080/hCLDN-6	Cancer cell line	Male
CVCL_D3PQ	CHO/CLDN6	Transformed cell line	Female
CVCL_E6PZ	Genomeditech CHO-K1 H_CLDN6	Spontaneously immortalized cell line	Female
CVCL_E6TQ	Genomeditech HEK-293 H_CLDN6	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.