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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.76

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CLDN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

268 rare PASS variants

Rare truncating (LoF)

1 in 6,800

18 rare PASS variants

Rare synonymous (reference)

1 in 530

153 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLDN3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 410	1 in 10,000
South Asian	~43k	1 in 320	1 in 5,000
Remaining (unassigned)	~30k	1 in 320	1 in 4,900
European (Finnish)	~27k	1 in 250	1 in 4,400
Admixed American	~22k	1 in 370	none seen
African / African American	~21k	1 in 190	1 in 3,100
East Asian	~20k	1 in 330	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 470	none seen
Middle Eastern	~2,884	≈ 1 in 960	≈ 1 in 1,300

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓