CLDN5

Chr 22

claudin 5

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

NCBI Gene: 7122 ENSG00000184113 UniProt: O00501 OMIM: 602101

This gene encodes claudin-5, an integral membrane protein that forms tight junction strands and plays a major role in obliterating the intercellular space to prevent solutes and water from passing freely between endothelial cell sheets. Mutations cause velocardiofacial syndrome, which follows an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants (pLI 0.90, LOEUF 0.41), indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.41

Clinical Summary— CLDN5

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.90) — some intolerance to loss-of-function variants.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.44Z-score

OE missense 0.68 (0.58–0.80)

108 obs / 159.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.41)

0≤0.351.4

Missense OE?0.68 (0.58–0.80)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 0 / 7.3Missense obs/exp: 108 / 159.0Syn Z: 0.38

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCLDN5-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.5772th %ile

GOF

0.73top 25%

LOF

0.4528th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThis mutation is the first gain-of-function mutation identified in the CLDN gene family with all others representing loss-of-function mutations resulting in mis-localization of CLDN protein and/or attenuated barrier function.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References