CLDN16

Chr 3AR

claudin 16

Also known as: HOMG3, PCLN1

NCBI Gene: 10686 ENSG00000113946 UniProt: Q9Y5I7 OMIM: 603959

Claudin-16 forms paracellular channels in kidney tight junctions that facilitate sodium permeability and drive magnesium and calcium reabsorption in the thick ascending limb of Henle's loop. Mutations cause autosomal recessive hypomagnesemia 3, characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. The gene shows relatively low constraint to loss-of-function variation (pLI 0.03, LOEUF 0.76).

OMIM ResearchSummary from RefSeq, OMIM, 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 gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.761 OMIM phenotype

Clinical Summary— CLDN16

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Gene-Disease Validity (ClinGen)

renal hypomagnesemia 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

59 unique Pathogenic / Likely Pathogenic· 181 VUS of 400 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.76LOEUF

pLI 0.025

Z-score 2.21

OE 0.36 (0.19–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.08Z-score

OE missense 1.02 (0.90–1.15)

173 obs / 170.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.36 (0.19–0.76)

0≤0.351.4

Missense OE?1.02 (0.90–1.15)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 5 / 13.9Missense obs/exp: 173 / 170.2Syn Z: -1.25

This gene — mechanism propensity

0.77top 25%

GOF

0.78top 25%

LOF

0.2582th %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

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic29

VUS181

Likely Benign81

Benign44

Conflicting18

Pathogenic

Likely Pathogenic

181

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	15	3	0	30
Likely Pathogenic	11	17	1	0	29
VUS	3	111	62	5	181
Likely Benign	0	3	38	40	81
Benign	0	2	37	5	44
Conflicting	—				18
Total	26	148	141	50	383

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap CLDN16 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →