CLDN5

Chr 22

claudin 5

Also known as: AWAL, BEC1, CPETRL1, TMDVCF, TMVCF

NCBI Gene: 7122ENSG00000184113UniProt: O00501

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. Mutations in this gene have been found in patients with velocardiofacial syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

442
ClinVar variants
384
Pathogenic / LP
0.90
pLI score
2
Active trials
Clinical Summary— CLDN5
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.90) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
384 Pathogenic / Likely Pathogenic· 48 VUS of 442 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.41LOEUF
pLI 0.895
Z-score 2.50
OE 0.00 (0.00–0.41)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.44Z-score
OE missense 0.68 (0.58–0.80)
108 obs / 159.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.58–0.80)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 0 / 7.3Missense obs/exp: 108 / 159.0Syn Z: 0.38

ClinVar Variant Classifications

442 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic373
Likely Pathogenic11
VUS48
Likely Benign7
Benign3
373
Pathogenic
11
Likely Pathogenic
48
VUS
7
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
370
0
373
Likely Pathogenic
0
2
9
0
11
VUS
1
26
21
0
48
Likely Benign
0
6
0
1
7
Benign
0
0
2
1
3
Total1374022442

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CLDN5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CLDN5-related neurodevelopmental disorder

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CLAUDIN 5; CLDN5
MIM #602101 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.
Dudek KA et al.·Proc Natl Acad Sci U S A
2020
The CLDN5 gene at the blood-brain barrier in health and disease.
Hashimoto Y et al.·Fluids Barriers CNS
2023Review
CLDN5: From structure and regulation to roles in tumors and other diseases beyond CNS disorders.
Ling Y et al.·Pharmacol Res
2024Review
Claudins and hepatocellular carcinoma.
Wang W et al.·Biomed Pharmacother
2024Review
Exploring potential genes and mechanisms linking erectile dysfunction and depression.
Yuan P et al.·Front Endocrinol (Lausanne)
2023Functional
Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications.
Deshwar AR et al.·Brain
2023
CD34(+)CLDN5(+) tumor associated senescent endothelial cells through IGF2-IGF2R signaling increased cholangiocellular phenotype in hepatocellular carcinoma.
Zhu XY et al.·J Adv Res
2025
Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.
Hashimoto Y et al.·Brain
2022
Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.
Gal Z et al.·Int J Neuropsychopharmacol
2023
MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.
Yang L et al.·Skin Res Technol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Atherosclerosis Cardiovascular DiseaseObesityMetabolic Syndrome

Deciphering the Effect of Moderate Wine Consumption on Healthy Aging Through Postprandial Extracellular Vesicles.

RECRUITING
NCT07361887Phase NAUniversity of SevilleStarted 2025-11-01
White WineRed WineWater
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools