CLDN1

protein-coding

claudin 1, the group of Claudins

Gene summary

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. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_021101.5

Inheritance

ClinVar variants

P:10U:57B:28

Top phenotype

Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:190,305,707-190,322,446

External References & Databases

Ensembl (ENSG00000163347)

Transcript & Mutation Effects

hg38 • Region Span ~16.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neonatal ichthyosis-sclerosing cholangitis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011874

Submitter: Orphanet

neonatal ichthyosis-sclerosing cholangitis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011874

Submitter: G2P

neonatal ichthyosis-sclerosing cholangitis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011874

Submitter: Genomics England PanelApp

neonatal ichthyosis-sclerosing cholangitis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011874

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitisAR

Manifestation: Dermatologic; Gastrointestinal

Intervention: Gastrointestinal

Rationale: Individuals can have manifest with hepatic disease, and liver transplantation has been described as beneficial; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12164927; 15521008; 16619213; 20645982; 21865982

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLDN1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 56

CLDN1-related disorderTotal: 36

Inborn genetic diseasesTotal: 31

Neonatal ichthyosis-sclerosing cholangitis syndromeTotal: 9

not specifiedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021101.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	21 clinvar	2 clinvar	27
missense		1 clinvar	52 clinvar	5 clinvar		58
nonsense	3 clinvar	3 clinvar	1 clinvar			7
start loss						0
frameshift	2 clinvar	1 clinvar				3
splice donor/acceptor (+/-2bp)						0
Total	5	5	57	26	2	95

Highest pathogenic variant AF is 0.000025400868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021101.5	RefSeq	NP_066924.1	4	MANE Select
ENST00000295522.4	Ensembl	ENSP00000295522.3	4	MANE Select
ENST00000981812.1	Ensembl	ENSP00000651629.1	4	Standard
ENST00000981813.1	Ensembl	ENSP00000651630.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)
Hepatitis C - Homo sapiens (human)
Leukocyte transendothelial migration - Homo sapiens (human)

Biological Process

aging
establishment of blood-nerve barrier
calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules
response to lipopolysaccharide
hyperosmotic salinity response

Molecular Function

virus receptor activity
structural molecule activity
protein binding
identical protein binding

Cellular Component

cytoplasm
integral component of plasma membrane
bicellular tight junction
integral component of membrane
basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295522
Coding exons: 4
Length: 16775
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0323	121	122	0.992	0.00000621	1362
Missense (PolyPhen)		54	46.777	1.1544		552
Synonymous	-0.134	50	48.8	1.02	0.00000282	434
Loss of Function	1.19	6	10.1	0.597	5.18e-7	100

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin. Required for normal water homeostasis and to prevent excessive water loss through the skin, probably via an indirect effect on the expression levels of other proteins, since CLDN1 itself seems to be dispensable for water barrier formation in keratinocyte tight junctions (PubMed:23407391). {ECO:0000269|PubMed:23407391}.;

Recessive Scores

pRec: 0.235

Intolerance Scores

LoFtool: 0.210
RVIS EVS: -0.12
RVIS percentile EVS: 44.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.938

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium