The protein is an integral membrane component of tight junctions that obliterates intercellular space between epithelial cells, forming barriers that prevent solutes and water from passing through paracellular spaces. Mutations in this gene have not been definitively associated with any recognized Mendelian disease or developmental disorder. The gene shows low constraint against loss-of-function variants (pLI 0.004, LOEUF 1.58), suggesting that heterozygous loss may be tolerated.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.58
Clinical SummaryCLDN6
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.58LOEUF
pLI 0.004
Z-score 0.60
OE 0.72 (0.351.58)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.43Z-score
OE missense 1.10 (0.961.26)
148 obs / 134.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.72 (0.351.58)
00.351.4
Missense OE1.10 (0.961.26)
00.61.4
Synonymous OE1.35
01.21.6
LoF obs/exp: 4 / 5.5Missense obs/exp: 148 / 134.0Syn Z: -2.18
DN
0.7325th %ile
GOF
0.76top 25%
LOF
0.2776th %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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

CLDN6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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