CLDN3

Chr 7

claudin 3

Also known as: C7orf1, CPE-R2, CPETR2, HRVP1, RVP1

NCBI Gene: 1365 ENSG00000165215 UniProt: O15551 OMIM: 602910

The protein is a barrier-forming claudin that plays a major role in tight junction formation by obliterating intercellular space through calcium-independent cell adhesion activity. Mutations cause autosomal recessive intellectual disability and hypocalciuric hypercalcemia, affecting neurological development and calcium homeostasis. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

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 intronless gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is also a low-affinity receptor for Clostridium perfringens enterotoxin, and shares aa sequence similarity with a putative apoptosis-related protein found in rat. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.76

Clinical Summary— CLDN3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.52) — some intolerance to loss-of-function variants.

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ClinVar Variants

34 VUS of 34 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.76LOEUF

pLI 0.522

Z-score 1.95

OE 0.16 (0.06–0.76)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.33Z-score

OE missense 0.70 (0.59–0.82)

106 obs / 152.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.06–0.76)

0≤0.351.4

Missense OE?0.70 (0.59–0.82)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 6.3Missense obs/exp: 106 / 152.0Syn Z: 1.15

This gene — mechanism propensity

0.74top 25%

GOF

0.78top 25%

LOF

0.2971th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

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

ClinVar Variant Classifications

34 submitted variants in ClinVar

ClinVar

Classification Summary

VUS34

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	34	34
Likely Benign	0	0
Benign	0	0
Total	34	34

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

View in ClinVar →

166 pathogenic / likely-pathogenic (of 172) ClinVar copy-number / structural variants overlap CLDN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →