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…

Primary Disease Associations & Inheritance

Hypomagnesemia 3, renalMIM #248250

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · renal hypomagnesemia 3 · AR · ClinGen 2023

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

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

Background carrier burden — how many people carry a rare variant somewhere in CLDN16?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

315 rare PASS variants

Rare truncating (LoF)

1 in 4,300

41 rare PASS variants

Rare synonymous (reference)

1 in 250

117 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLDN16. 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 300	1 in 4,100
South Asian	~43k	1 in 220	1 in 4,800
Remaining (unassigned)	~30k	1 in 160	1 in 4,300
European (Finnish)	~27k	1 in 1,500	1 in 5,300
Admixed American	~22k	1 in 170	≈ 1 in 7,500
African / African American	~21k	1 in 110	≈ 1 in 4,400
East Asian	~20k	1 in 260	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 730	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 180	none seen

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 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓