CLDN12

Summary

CLDN12 (claudin 12, HGNC:2034) is a protein-coding gene on chromosome 7q21.13, encoding Claudin-12 (P56749). Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.

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 expressed in the inner ear and bladder epithelium, and it is over-expressed in colorectal carcinomas. This protein and claudin 2 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Multiple alternatively spliced transcript variants encoding the same protein have been found.

Source: NCBI Gene 9069 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_001185072

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2034
Approved symbol	CLDN12
Name	claudin 12
Location	7q21.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000157224
Ensembl biotype	protein_coding
OMIM	611232
Entrez	9069

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 35 protein_coding, 8 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000287916, ENST00000394604, ENST00000394605, ENST00000416322, ENST00000427904, ENST00000451941, ENST00000462636, ENST00000476475, ENST00000478752, ENST00000483862, ENST00000485696, ENST00000495768, ENST00000496677, ENST00000498033, ENST00000498326, ENST00000905674, ENST00000905675, ENST00000905676, ENST00000905677, ENST00000905678, ENST00000905679, ENST00000905680, ENST00000905681, ENST00000905682, ENST00000905683, ENST00000905684, ENST00000920318, ENST00000920319, ENST00000920320, ENST00000920321, ENST00000920322, ENST00000920323, ENST00000920324, ENST00000944964, ENST00000944965, ENST00000944966, ENST00000944967, ENST00000944968, ENST00000944969, ENST00000944970, ENST00000944971, ENST00000944972, ENST00000944973, ENST00000944974

RefSeq mRNA: 3 — MANE Select: NM_001185072 NM_001185072, NM_001185073, NM_012129

CCDS: CCDS5618

Canonical transcript exons

ENST00000496677 — 4 exons

Exon	Start	End
ENSE00001387830	90405519	90405608
ENSE00001518982	90412644	90415954
ENSE00001830322	90412007	90412049
ENSE00001852252	90403461	90403549

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4030 / max 348.0970, expressed in 1699 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79450	16.7946	1674
79451	5.7593	1376
79453	0.4152	242
79454	0.2167	70
79455	0.2077	66
79449	0.0095	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.42	gold quality
adrenal tissue	UBERON:0018303	96.86	gold quality
islet of Langerhans	UBERON:0000006	96.35	gold quality
oocyte	CL:0000023	95.63	gold quality
epithelial cell of pancreas	CL:0000083	94.75	gold quality
cartilage tissue	UBERON:0002418	93.69	gold quality
oviduct epithelium	UBERON:0004804	93.47	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.09	gold quality
right lobe of liver	UBERON:0001114	92.92	gold quality
rectum	UBERON:0001052	91.97	gold quality
colonic mucosa	UBERON:0000317	91.95	gold quality
pituitary gland	UBERON:0000007	91.47	gold quality
adenohypophysis	UBERON:0002196	91.20	gold quality
left ventricle myocardium	UBERON:0006566	91.19	silver quality
ileal mucosa	UBERON:0000331	90.98	gold quality
nasal cavity epithelium	UBERON:0005384	90.80	silver quality
pancreas	UBERON:0001264	90.74	gold quality
liver	UBERON:0002107	90.74	gold quality
gall bladder	UBERON:0002110	90.72	gold quality
deltoid	UBERON:0001476	90.54	gold quality
left adrenal gland	UBERON:0001234	90.16	gold quality
bronchial epithelial cell	CL:0002328	90.03	gold quality
minor salivary gland	UBERON:0001830	89.99	gold quality
calcaneal tendon	UBERON:0003701	89.86	gold quality
caput epididymis	UBERON:0004358	89.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.66	gold quality
left adrenal gland cortex	UBERON:0035825	89.55	gold quality
adrenal gland	UBERON:0002369	89.33	gold quality
tibialis anterior	UBERON:0001385	89.32	gold quality
right adrenal gland	UBERON:0001233	89.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.47
E-MTAB-6386	no	33.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

198 targeting CLDN12, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-8068	99.98	73.85	2376
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593

Literature-anchored findings (GeneRIF, showing 7)

• Differential expression of genes encoding claudins in colorectal cancer suggests that these tight junction proteins may be associated to and involved in tumorigenesis. (PMID:17047970)
• These findings strongly suggest that claudin-2- and/or claudin-12-based tight junctions form paracellular Ca(2+) channels in intestinal epithelia, and they highlight a novel mechanism behind vitamin D-dependent calcium homeostasis. (PMID:18287530)
• Knockdown of claudin-3, claudin-4, and claudin-12, but not claudin-1, increased breast cancer MCF-7 cell migration with maximal effects observed in claudin-12 siRNA-transfected cells. (PMID:25727011)
• CLDN 12 expression could be clinically useful for predicting the survival of the estrogen receptor (ER)-negative subgroup of patients with breast cancer. (PMID:26926102)
• We found that COPII cargo CLDN12 is important for Hepatitis C Virus entry. (PMID:30339745)
• Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer. (PMID:33917356)
• Tight Junction Protein Claudin-12 Is Involved in Cell Migration during Metastasis. (PMID:33922921)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cldn12	ENSDARG00000003927
mus_musculus	Cldn12	ENSMUSG00000046798
rattus_norvegicus	Cldn12	ENSRNOG00000039862

Protein

Protein identifiers

Claudin-12 — P56749 (reviewed: P56749)

All UniProt accessions (4): P56749, A8MX62, C9J4P0, C9J841

UniProt curated annotations — full annotation on UniProt →

Function. Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.

Subunit / interactions. Interacts with OCLN.

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

Similarity. Belongs to the claudin family.

RefSeq proteins (3): NP_001172001, NP_001172002, NP_036261 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013287	Claudin12	Family
IPR017974	Claudin_CS	Conserved_site

UniProt features (12 total): topological domain 5, transmembrane region 4, modified residue 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56749-F1	80.85	0.58

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 (2): 228, 231

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 189 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION, RYTTCCTG_ETS2_B, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_CELL_JUNCTION_ASSEMBLY, SENESE_HDAC1_TARGETS_UP, ZHANG_BREAST_CANCER_PROGENITORS_UP, GOBP_CELL_CELL_JUNCTION_ASSEMBLY, GOCC_CELL_CELL_JUNCTION, CHANG_IMMORTALIZED_BY_HPV31_UP, GOBP_HOMEOSTATIC_PROCESS, GOCC_LATERAL_PLASMA_MEMBRANE, GOCC_ANCHORING_JUNCTION

GO Biological Process (2): calcium-independent cell-cell adhesion (GO:0016338), maintenance of blood-brain barrier (GO:0035633)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), lateral plasma membrane (GO:0016328), membrane (GO:0016020), tight junction (GO:0070160), anchoring junction (GO:0070161), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-cell junction organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell-cell adhesion	1
tissue homeostasis	1
protein binding	1
binding	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
plasma membrane	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

1324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN12	CLDN3	O15551	982
CLDN12	CLDN4	O14493	958
CLDN12	CLDN2	P57739	934
CLDN12	CLDN8	P56748	929
CLDN12	CLDN1	O95832	922
CLDN12	CLDN5	O00501	918
CLDN12	TJP1	Q07157	901
CLDN12	CLDN7	O95471	888
CLDN12	TJP2	Q9UDY2	846
CLDN12	CLDN17	P56750	823
CLDN12	OCLN	Q16625	810
CLDN12	CLDN15	P56746	781
CLDN12	TJP3	O95049	735
CLDN12	CLDN9	O95484	688
CLDN12	CLDN6	P56747	650

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TUSC5	CLDN12	psi-mi:“MI:0915”(physical association)	0.560
CLDN12	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
CLDN12	SEC13	psi-mi:“MI:0915”(physical association)	0.370
CLDN12		psi-mi:“MI:0915”(physical association)	0.370
FUCA2	UQCRH	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
TUSC5	CLDN12	psi-mi:“MI:0915”(physical association)	0.000
STRN4	CLDN12	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): CLDN12 (Affinity Capture-MS), CLDN12 (Affinity Capture-RNA), CLDN12 (Affinity Capture-RNA), CLDN12 (Two-hybrid), TUSC5 (Two-hybrid), CLDN12 (Affinity Capture-MS), CLDN12 (Affinity Capture-MS), CLDN12 (Negative Genetic), CLDN12 (Affinity Capture-RNA), CLDN12 (Two-hybrid), CLDN12 (Proximity Label-MS), CLDN12 (Affinity Capture-RNA), CLDN12 (Proximity Label-MS), CLDN12 (Affinity Capture-RNA), ECHS1 (Two-hybrid)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A9UL59, B2RVW2, B4L184, B4LC58, B4N5D3, D3ZFW5, O95473, P23290, P35801, P35802, P35803, P36964, P36965, P51674, P56749, P58418, P79826, Q0IIL2, Q0P4G7, Q0VD07, Q11085, Q13491, Q2YDD6, Q53R12, Q5R603, Q5R9K1, Q5R9Q3, Q5R9R3, Q5T9L3, Q5ZLR1, Q6AYR5, Q6CRM6, Q6DID7, Q6P689, Q6UX40, Q754N9, Q7YWX7, Q812E9

Diamond homologs: P56749, Q0IIL2, Q5R9K1, Q9ET43

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

727 predictions. Top by Δscore:

Variant	Effect	Δscore
7:90385038:G:GT	donor_gain	1.0000
7:90385039:A:T	donor_gain	1.0000
7:90403546:GCAG:G	donor_gain	1.0000
7:90403547:CAGG:C	donor_loss	1.0000
7:90403548:AGG:A	donor_loss	1.0000
7:90403549:GG:G	donor_loss	1.0000
7:90403550:GTAG:G	donor_loss	1.0000
7:90403516:TGGGC:T	donor_gain	0.9900
7:90403517:GGGCG:G	donor_gain	0.9900
7:90412642:A:AG	acceptor_gain	0.9900
7:90412643:G:GG	acceptor_gain	0.9900
7:90384890:A:AG	acceptor_gain	0.9800
7:90384891:G:GG	acceptor_gain	0.9800
7:90403505:GCTCC:G	donor_gain	0.9800
7:90405516:TAGGC:T	acceptor_gain	0.9800
7:90405517:AGGCT:A	acceptor_gain	0.9800
7:90405607:GC:G	donor_gain	0.9800
7:90412643:GTCT:G	acceptor_gain	0.9800
7:90403520:C:T	donor_gain	0.9700
7:90384886:TTTTA:T	acceptor_loss	0.9600
7:90384887:TTTAG:T	acceptor_loss	0.9600
7:90384888:TTAG:T	acceptor_loss	0.9600
7:90384889:TAG:T	acceptor_loss	0.9600
7:90384890:A:AC	acceptor_loss	0.9600
7:90384891:G:GT	acceptor_loss	0.9600
7:90385065:T:G	donor_gain	0.9500
7:90405609:G:GG	donor_gain	0.9500
7:90412642:AGTCT:A	acceptor_gain	0.9500
7:90412643:GTCTG:G	acceptor_gain	0.9500
7:90384877:T:TA	acceptor_loss	0.9400

AlphaMissense

1567 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:90412725:G:A	G17R	0.999
7:90412725:G:C	G17R	0.999
7:90412773:T:A	W33R	0.999
7:90412773:T:C	W33R	0.999
7:90412775:G:C	W33C	0.999
7:90412775:G:T	W33C	0.999
7:90412778:A:C	R34S	0.999
7:90412778:A:T	R34S	0.999
7:90412839:T:A	W55R	0.999
7:90412839:T:C	W55R	0.999
7:90412898:G:C	W74C	0.999
7:90412898:G:T	W74C	0.999
7:90413217:A:C	S181R	0.999
7:90413219:T:A	S181R	0.999
7:90413219:T:G	S181R	0.999
7:90412726:G:A	G17E	0.998
7:90412743:G:C	G23R	0.998
7:90412744:G:A	G23D	0.998
7:90412755:G:T	G27W	0.998
7:90412777:G:C	R34T	0.998
7:90412833:G:C	G53R	0.998
7:90412833:G:T	G53C	0.998
7:90412834:G:T	G53V	0.998
7:90412841:G:C	W55C	0.998
7:90412841:G:T	W55C	0.998
7:90412848:T:A	C58S	0.998
7:90412849:G:C	C58S	0.998
7:90412875:T:A	C67S	0.998
7:90412875:T:C	C67R	0.998
7:90412876:G:C	C67S	0.998

dbSNP variants (sampled 300 via entrez): RS1000392476 (7:90406135 T>C), RS1000492826 (7:90410516 AT>A), RS1000602051 (7:90403743 G>A,T), RS1000928956 (7:90411590 G>T), RS1000960142 (7:90404778 T>C), RS1000970849 (7:90411152 T>A,G), RS1001231151 (7:90416431 A>T), RS1001281635 (7:90409388 G>A,C), RS1001598851 (7:90416227 T>C), RS1001667620 (7:90407194 C>T), RS1001887137 (7:90411659 A>C,T), RS1002255057 (7:90404318 A>T), RS1002267391 (7:90405655 C>T), RS1002448771 (7:90404070 C>A,G,T), RS1002551520 (7:90415190 G>A,T)

Disease associations

OMIM: gene MIM:611232 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
diallyl trisulfide	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Troglitazone	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Aerosols	increases expression	1
Air Pollutants	increases expression, affects cotreatment, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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