CLDN16

Summary

CLDN16 (claudin 16, HGNC:2037) is a protein-coding gene on chromosome 3q28, encoding Claudin-16 (Q9Y5I7). Forms paracellular channels: coassembles with CLDN19 into tight junction strands with cation-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.

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.

Source: NCBI Gene 10686 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal hypomagnesemia 3 (Definitive, ClinGen)
• Clinical variants (ClinVar): 291 total — 26 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 60
• MANE Select transcript: NM_006580

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2037
Approved symbol	CLDN16
Name	claudin 16
Location	3q28
Locus type	gene with protein product
Status	Approved
Aliases	PCLN1, HOMG3
Ensembl gene	ENSG00000113946
Ensembl biotype	protein_coding
OMIM	603959
Entrez	10686

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000264734, ENST00000456423, ENST00000468220, ENST00000880223, ENST00000880224, ENST00000880225, ENST00000880226, ENST00000880227, ENST00000880228, ENST00000880229, ENST00000880230, ENST00000962254, ENST00000962255, ENST00000962256, ENST00000962257

RefSeq mRNA: 3 — MANE Select: NM_006580 NM_001378492, NM_001378493, NM_006580

CCDS: CCDS3296

Canonical transcript exons

ENST00000264734 — 5 exons

Exon	Start	End
ENSE00000781631	190404762	190404926
ENSE00000781632	190408314	190408505
ENSE00001073608	190388163	190388443
ENSE00001218576	190409903	190412138
ENSE00003581392	190402337	190402439

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 78.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6668 / max 1037.7659, expressed in 63 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40556	0.6949	18
40552	0.5814	41
40558	0.1968	17
40555	0.0489	8
40550	0.0482	33
40557	0.0480	8
40551	0.0263	17
40554	0.0223	11

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.35	gold quality
adult mammalian kidney	UBERON:0000082	77.42	gold quality
buccal mucosa cell	CL:0002336	71.41	silver quality
metanephros cortex	UBERON:0010533	70.11	gold quality
kidney	UBERON:0002113	69.53	gold quality
skin of abdomen	UBERON:0001416	68.90	gold quality
skin of leg	UBERON:0001511	66.31	gold quality
right uterine tube	UBERON:0001302	64.90	gold quality
bronchial epithelial cell	CL:0002328	64.64	gold quality
zone of skin	UBERON:0000014	64.03	gold quality
right adrenal gland cortex	UBERON:0035827	63.99	gold quality
hair follicle	UBERON:0002073	63.96	gold quality
left adrenal gland	UBERON:0001234	63.46	gold quality
right adrenal gland	UBERON:0001233	63.42	gold quality
smooth muscle tissue	UBERON:0001135	63.24	gold quality
left adrenal gland cortex	UBERON:0035825	62.62	gold quality
epithelium of bronchus	UBERON:0002031	62.48	gold quality
gall bladder	UBERON:0002110	62.32	gold quality
bronchus	UBERON:0002185	61.68	gold quality
islet of Langerhans	UBERON:0000006	61.65	gold quality
adrenal cortex	UBERON:0001235	61.32	gold quality
left uterine tube	UBERON:0001303	60.55	gold quality
adrenal gland	UBERON:0002369	60.36	gold quality
metanephros	UBERON:0000081	59.72	gold quality
right lobe of liver	UBERON:0001114	59.52	gold quality
cortex of kidney	UBERON:0001225	59.06	gold quality
nasal cavity mucosa	UBERON:0001826	57.93	gold quality
lymph node	UBERON:0000029	57.54	gold quality
male germ cell	CL:0000015	56.56	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	763.13
E-GEOD-131882	yes	761.72
E-HCAD-10	yes	12.36
E-ANND-3	yes	3.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT1

miRNA regulators (miRDB)

137 targeting CLDN16, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7D-5P	99.96	71.76	1632

Literature-anchored findings (GeneRIF, showing 30)

• Mutations in claudin 16 that affect interaction with ZO-1 lead to lysosomal mistargeting (PMID:14628289)
• Paracellin-1 modulates paracellular conductance and not transcellular transport; it does not form magnesium ion-selective paracellular channels (PMID:16234325)
• We conclude that FHHNC can result from mutations in Cldn16 that affect intracellular trafficking or paracellular Mg2+ permeability (PMID:16528408)
• We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. (PMID:16924549)
• paracellin-1 might act as selectivity filter for the paracellular movement of ions and water during stimulated secretion (PMID:17551748)
• Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations (PMID:18003771)
• Claudin-16 plays a role beyond that of an initial metastasis repressor in this cancer type (PMID:18442037)
• Mutation analysis reveals compound heterozygous mutations in the claudin 16 gene (CLDN16) in two siblings affecting the second extracellular loop of claudin 16 and leading to complete loss of the protein. (PMID:18816383)
• The expression of claudins-2, -3 and -4 in 16 rectal well-differentiated endocrine neoplasms was studied (PMID:19082451)
• Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: unusual clinical associations and novel claudin16 mutation in an Egyptian family. (PMID:19165416)
• Mg(2+) depletion markedly increased and Mg(2+) load decreased endogenous claudin-16 mRNA levels in calcium-sensing receptor-transfected HEK293 cells compared with native HEK293 cells. (PMID:20511716)
• Elevated CLDN16 gene expression was suggested to be involved in the development of breast cancer and to be a biomarker and target treatment for breast cancer. (PMID:20664984)
• Multiple distinct mutations in the CLDN16 and CLDN19 genes have been found responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis. (PMID:21186073)
• A novel mutation of CLDN16 gene is responsible for familial hypomagnesaemia in Turkish children. (PMID:21669885)
• Claudin-16 plays a role beyond that of an initial metastasis repressor in breast cancer. (PMID:21717372)
• Claudin 16 gene revealed homozygosity for the p.K183E(AAA>GAA) C. 547A>G indicating the diagnosis of hypomagnesemia with hypercalciuria and nephrocalcinosis. (PMID:21848011)
• Six different mutations of CLDN16 were detected (five missense and one nonsense); three of the missense mutations were previously unknown (p.Cys80Tyr, p.Lys183Glu, and p.Gly233Arg). (PMID:22422540)
• A novel CLDN16 mutation has been identified in a large consanguineous family with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. (PMID:24321194)
• These results suggest that STX8 mediates the recycling of CLDN16 and constitutes an important component of the CLDN16 trafficking machinery in the kidney. (PMID:24659781)
• CLDN16 mutations are associated with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. (PMID:25477417)
• 1,25(OH)2 VitD transcriptionally inhibits renal claudin-16 expression by a mechanism sensitive to CaSR and Mg(2+). (PMID:25557732)
• claudin-16 gene (CLDN16) mutations result in amelogenesis imperfect. (PMID:26426912)
• detected a novel mutation in CLDN16 for the first time. The clinical and genetic findings from this study will help to expand the understanding of this rare disease, FHHNC (PMID:27067446)
• Data suggest that Pdzrn3 mediates endocytosis of dephosphorylated CLDN16 and represents an important component of CLDN16-trafficking machinery in renal tube epithelial cells. (Pdzrn3 = PDZ domain containing RING finger 3 protein; CLDN16 = claudin 16) (PMID:28623232)
• This study demonstrated that a female-specific role clnd16 in tau pathology (PMID:29967939)
• No significant associations were found among claudin-16 and claudin-19 single-nucleotide polymorphisms and calcium excretion and between claudin-14, claudin-16, and claudin-19 single-nucleotide polymorphisms and stones. (PMID:30232134)
• Results show that CLDN16 mutation c.602G>A had no effect on pre-mRNA splicing in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. This study expands the genotypic classification of this rare disease and provides the first report of a CLDN19 mutation affecting splicing. (PMID:30576809)
• Mutations in CLDN16 that encodes claudin-16, a tight-junction protein involved in paracellular reabsorption of magnesium and calcium in the renal tubule. (PMID:30621608)
• To gain more understanding about the mechanisms by which CLDN16 mutations can induce FHHNC, we performed an in-depth computational analysis of the CLDN16 gene and protein, focusing specifically on the prediction of the latter’s subcellular localization. (PMID:31357502)
• A Novel Mutation in CLDN16 Gene Causing Familial Hypomagnesemia, Hypercalciuria, Nephrocalcinosis in An Iranian Family. (PMID:35714216)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cldn16	ENSMUSG00000038148
rattus_norvegicus	Cldn16	ENSRNOG00000055138

Paralogs (22): CLDN11 (ENSG00000013297), CLDN18 (ENSG00000066405), CLDN15 (ENSG00000106404), CLDN10 (ENSG00000134873), CLDN17 (ENSG00000156282), CLDN8 (ENSG00000156284), CLDN14 (ENSG00000159261), CLDN1 (ENSG00000163347), CLDN19 (ENSG00000164007), CLDN3 (ENSG00000165215), CLDN2 (ENSG00000165376), CLDN20 (ENSG00000171217), CLDN22 (ENSG00000177300), CLDN7 (ENSG00000181885), CLDN5 (ENSG00000184113), CLDN6 (ENSG00000184697), CLDN24 (ENSG00000185758), CLDN4 (ENSG00000189143), CLDN9 (ENSG00000213937), CLDN25 (ENSG00000228607), CLDN34 (ENSG00000234469), CLDN23 (ENSG00000253958)

Protein

Protein identifiers

Claudin-16 — Q9Y5I7 (reviewed: Q9Y5I7)

Alternative names: Paracellin-1

All UniProt accessions (2): Q9Y5I7, F6SGM4

UniProt curated annotations — full annotation on UniProt →

Function. Forms paracellular channels: coassembles with CLDN19 into tight junction strands with cation-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability. Involved in the maintenance of ion gradients along the nephron. In the thick ascending limb (TAL) of Henle’s loop, facilitates sodium paracellular permeability from the interstitial compartment to the lumen, contributing to the lumen-positive transepithelial potential that drives paracellular magnesium and calcium reabsorption.

Subunit / interactions. Can form heteropolymeric tight junction strands with other claudins. Interacts with CLDN19. Interacts (via PDZ-binding motif TRV) with TJP1 (via PDZ domain). Cannot form tight junction strands on its own.

Subcellular location. Cell junction. Tight junction. Cell membrane.

Tissue specificity. Kidney-specific, including the thick ascending limb of Henle (TAL).

Disease relevance. Hypomagnesemia 3 (HOMG3) [MIM:248250] A progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis. Recurrent urinary tract infections and kidney stones are often observed. In spite of hypercalciuria, patients do not show hypocalcemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The first extracellular loop (25-79) contains negatively charged amino acids that affect cation selectivity.

Similarity. Belongs to the claudin family.

RefSeq proteins (3): NP_001365421, NP_001365422, NP_006571* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003927	Claudin16	Family
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

Catalyzed reactions (Rhea), 7 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Li(+)(in) = Li(+)(out) (RHEA:78551)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (48 total): sequence variant 22, mutagenesis site 15, topological domain 5, transmembrane region 4, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5I7-F1	76.74	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (15):

Position	Phenotype
27	low protein expression mostly retained in the endoplasmic reticulum; loss of paracellular sodium-selective transport.
34	localizes at tight junctions; partial loss of paracellular sodium-selective transport.
35	localizes at tight junctions; partial loss of paracellular sodium-selective transport.
38	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
42	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
44	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
49	localizes at tight junctions; partial loss of paracellular sodium-selective transport.
56	localizes at tight junctions; partial loss of paracellular sodium-selective transport.
59	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
62	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
63	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
65	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
70	localizes at tight junctions; partial loss of paracellular sodium-selective transport.
74	no significant effect on protein subcellular localization or paracellular sodium-selective transport.
79	low protein expression mostly retained in the endoplasmic reticulum; loss of paracellular sodium-selective transport.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 252 (showing top): CCAWYNNGAAR_UNKNOWN, KEGG_TIGHT_JUNCTION, GOBP_MAGNESIUM_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_ADHESION, BACH2_01, TGANTCA_AP1_C, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_RENAL_ABSORPTION, GOCC_CELL_CELL_JUNCTION, GOBP_TRANSMEMBRANE_TRANSPORT, KEGG_CELL_ADHESION_MOLECULES_CAMS, GOBP_RENAL_SYSTEM_PROCESS, GOBP_HOMEOSTATIC_PROCESS, WGGAATGY_TEF1_Q6

GO Biological Process (10): cell adhesion (GO:0007155), intercellular transport (GO:0010496), calcium-independent cell-cell adhesion (GO:0016338), metal ion transport (GO:0030001), intracellular monoatomic cation homeostasis (GO:0030003), renal absorption (GO:0070293), bicellular tight junction assembly (GO:0070830), paracellular transport (GO:0160184), monoatomic ion transport (GO:0006811), magnesium ion transmembrane transport (GO:1903830)

GO Molecular Function (6): structural molecule activity (GO:0005198), magnesium ion transmembrane transporter activity (GO:0015095), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), paracellular tight junction channel activity (GO:0160187), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), tight junction (GO:0070160), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-cell junction organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
cellular process	2
cell-cell adhesion	1
monoatomic cation transport	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
renal system process	1
apical junction assembly	1
tight junction assembly	1
magnesium ion transport	1
monoatomic cation transmembrane transport	1
molecular_function	1
metal ion transmembrane transporter activity	1
magnesium ion transmembrane transport	1
protein domain specific binding	1
protein binding	1
transporter activity	1
binding	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
cell-cell junction	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN16	CLDN19	Q8N6F1	972
CLDN16	FXYD2	P54710	923
CLDN16	TJP1	Q07157	877
CLDN16	SLC12A3	P55017	874
CLDN16	TRPM6	Q9BX84	828
CLDN16	OCLN	Q16625	708
CLDN16	PTH	P01270	696
CLDN16	FGF12	P61328	663
CLDN16	SLC41A1	Q8IVJ1	663
CLDN16	CASR	P41180	662
CLDN16	CLDN5	O00501	651
CLDN16	CNNM2	Q9H8M5	647
CLDN16	CLDN3	O15551	641
CLDN16	CLDN23	Q96B33	630
CLDN16	CLCNKB	P51801	629

IntAct

6 interactions, top by confidence:

A	B	Type	Score
Cldn14	CLDN16	psi-mi:“MI:0915”(physical association)	0.510
CLDN16	Cldn14	psi-mi:“MI:0915”(physical association)	0.510
CLDN16	Cldn10	psi-mi:“MI:0407”(direct interaction)	0.410
CLDN16	CLDN19	psi-mi:“MI:0407”(direct interaction)	0.410
CLDN19	CLDN16	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): Pdzrn3 (Reconstituted Complex), CLDN16 (Affinity Capture-Western), APP (Reconstituted Complex)

ESM2 similar proteins: A0A8M2B5N2, A0A8V0ZLT4, A1L157, O00322, O60637, O75841, P11049, P19075, P21926, P30409, P30413, P30932, P31053, P38572, P38573, P40239, P40240, P40241, Q0D289, Q2KHY8, Q2MJQ7, Q3SZR9, Q4R4Z3, Q4R7W6, Q566D0, Q568Y5, Q58CY8, Q5RDV7, Q5RE11, Q5RH71, Q61470, Q6AYR9, Q6GQF5, Q6P0C6, Q6ZUX7, Q80WR1, Q8WMQ3, Q91Y55, Q925N4, Q96FX8

Diamond homologs: A0A8C0N7E5, A6NM45, C3VMW3, C9JDP6, D3ZQJ0, O00501, O14493, O15551, O19005, O35054, O54942, O75508, O88551, O88552, O95471, O95484, O95500, O95832, P56745, P56746, P56747, P56748, P56750, P56856, P56857, P56880, P57739, P78369, Q0VCN0, Q2HJ22, Q2KIY2, Q3B7N4, Q3MHK4, Q4R3L1, Q5E9L0, Q5I0E5, Q5QT56, Q5R8E5, Q63400, Q6BBL6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

291 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	21
Uncertain significance	130
Likely benign	52
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1199406	NM_006580.4(CLDN16):c.236G>A (p.Arg79Gln)	Pathogenic
1396298	NM_021101.5(CLDN1):c.53G>A (p.Trp18Ter)	Pathogenic
2425616	NC_000003.11:g.(?190120106)(190127825_?)del	Pathogenic
30405	NM_006580.4(CLDN16):c.613A>T (p.Lys205Ter)	Pathogenic
3250410	NM_006580.4(CLDN16):c.374T>C (p.Leu125Pro)	Pathogenic
3359186	NM_006580.4(CLDN16):c.165del (p.Phe55fs)	Pathogenic
3390939	NM_006580.4(CLDN16):c.152T>G (p.Val51Gly)	Pathogenic
438693	NM_006580.4(CLDN16):c.468del (p.Gly157fs)	Pathogenic
545703	NM_006580.4(CLDN16):c.335_338dup (p.Lys113delinsAsnTer)	Pathogenic
560390	NM_006580.4(CLDN16):c.392G>A (p.Gly131Glu)	Pathogenic
5925	NM_006580.4(CLDN16):c.235C>T (p.Arg79Ter)	Pathogenic
5926	NM_006580.4(CLDN16):c.505G>A (p.Gly169Arg)	Pathogenic
5927	NM_006580.4(CLDN16):c.361G>A (p.Gly121Arg)	Pathogenic
5929	NM_006580.4(CLDN16):c.2T>G (p.Met1Arg)	Pathogenic
5930	NM_006580.4(CLDN16):c.290T>C (p.Leu97Pro)	Pathogenic
5932	NM_006580.4(CLDN16):c.488G>A (p.Gly163Asp)	Pathogenic
5933	NM_006580.4(CLDN16):c.494C>T (p.Ser165Phe)	Pathogenic
5934	NM_006580.4(CLDN16):c.243G>T (p.Leu81Phe)	Pathogenic
5935	NM_006580.4(CLDN16):c.242T>G (p.Leu81Trp)	Pathogenic
5936	NM_006580.4(CLDN16):c.224T>C (p.Leu75Pro)	Pathogenic
5937	NM_006580.4(CLDN16):c.140G>A (p.Trp47Ter)	Pathogenic
5938	NM_006580.4(CLDN16):c.453G>T (p.Leu151Phe)	Pathogenic
5939	NM_006580.4(CLDN16):c.698C>G (p.Thr233Arg)	Pathogenic
5940	NM_006580.4(CLDN16):c.621T>G (p.Tyr207Ter)	Pathogenic
6088	NM_021101.5(CLDN1):c.200_201del (p.Val66_Phe67insTer)	Pathogenic
932893	NM_006580.4:c.(?598)(900_?)del	Pathogenic
1202637	NM_006580.4(CLDN16):c.137T>C (p.Leu46Pro)	Likely pathogenic
1202638	NM_006580.4(CLDN16):c.103G>A (p.Asp35Asn)	Likely pathogenic
1324089	NM_006580.4(CLDN16):c.494C>A (p.Ser165Tyr)	Likely pathogenic
1464906	NM_006580.4(CLDN16):c.415G>A (p.Ala139Thr)	Likely pathogenic

SpliceAI

1004 predictions. Top by Δscore:

Variant	Effect	Δscore
3:190402440:G:GG	donor_gain	1.0000
3:190404924:CAG:C	donor_loss	1.0000
3:190404925:AG:A	donor_loss	1.0000
3:190404926:GG:G	donor_loss	1.0000
3:190404927:GTACC:G	donor_loss	1.0000
3:190404928:T:G	donor_loss	1.0000
3:190398344:G:GT	donor_gain	0.9900
3:190402174:G:T	donor_gain	0.9900
3:190402438:CT:C	donor_gain	0.9900
3:190404739:A:AG	acceptor_gain	0.9900
3:190404746:T:G	acceptor_gain	0.9900
3:190404751:T:TA	acceptor_gain	0.9900
3:190404760:A:AG	acceptor_gain	0.9900
3:190404760:AGT:A	acceptor_gain	0.9900
3:190404761:G:GA	acceptor_gain	0.9900
3:190404761:GT:G	acceptor_gain	0.9900
3:190404761:GTG:G	acceptor_gain	0.9900
3:190406000:T:TA	donor_gain	0.9900
3:190406001:A:AA	donor_gain	0.9900
3:190388439:TGGAG:T	donor_loss	0.9800
3:190388440:GGAGG:G	donor_loss	0.9800
3:190388441:GAGGT:G	donor_loss	0.9800
3:190388442:AGGTA:A	donor_loss	0.9800
3:190388443:GG:G	donor_loss	0.9800
3:190388444:GTAAG:G	donor_loss	0.9800
3:190388445:T:A	donor_loss	0.9800
3:190404740:A:G	acceptor_gain	0.9800
3:190404757:TCCA:T	acceptor_loss	0.9800
3:190404761:GTGA:G	acceptor_gain	0.9800
3:190404761:GTGAA:G	acceptor_gain	0.9800

AlphaMissense

1967 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:190402363:G:C	W117C	0.998
3:190402363:G:T	W117C	0.998
3:190388416:G:C	W99C	0.997
3:190388416:G:T	W99C	0.997
3:190402340:A:C	S110R	0.994
3:190402342:C:A	S110R	0.994
3:190402342:C:G	S110R	0.994
3:190402361:T:A	W117R	0.994
3:190402361:T:C	W117R	0.994
3:190408445:G:T	G242W	0.994
3:190408446:G:A	G242E	0.994
3:190402355:G:C	G115R	0.993
3:190402355:G:T	G115C	0.993
3:190402349:T:C	C113R	0.992
3:190408425:C:T	S235F	0.992
3:190388414:T:A	W99R	0.991
3:190388414:T:C	W99R	0.991
3:190402353:G:C	R114P	0.991
3:190402370:T:A	C120S	0.991
3:190402371:G:C	C120S	0.991
3:190408332:G:A	G204D	0.991
3:190408419:G:A	G233D	0.991
3:190402370:T:C	C120R	0.990
3:190402403:T:A	C131S	0.990
3:190402404:G:C	C131S	0.990
3:190408322:G:A	G201R	0.990
3:190408322:G:C	G201R	0.990
3:190408419:G:T	G233V	0.990
3:190402359:T:A	L116H	0.989
3:190404797:G:C	A155P	0.989

dbSNP variants (sampled 300 via entrez): RS1000023308 (3:190364693 T>C), RS1000029069 (3:190290143 T>C), RS1000077427 (3:190364841 G>A), RS1000097266 (3:190290826 G>A,C), RS1000135801 (3:190388929 G>A,T), RS1000153153 (3:190412588 A>G), RS1000154096 (3:190347988 A>G,T), RS1000200686 (3:190309368 C>A), RS1000238218 (3:190390175 T>C), RS1000250529 (3:190316036 C>A,G), RS1000254071 (3:190396370 T>A), RS1000264955 (3:190358914 C>A,T), RS1000275578 (3:190341522 A>G), RS1000277752 (3:190377800 G>A), RS1000343559 (3:190302836 T>C)

Disease associations

OMIM: gene MIM:603959 | disease phenotypes: MIM:248250, MIM:616216, MIM:607626, MIM:248190

GenCC curated gene-disease

Disease	Classification	Inheritance
renal hypomagnesemia 3	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
renal hypomagnesemia 3	Definitive	AR

Mondo (6): renal hypomagnesemia 3 (MONDO:0009550), thrombocytopenia 5 (MONDO:0014536), nephrocalcinosis (MONDO:0001567), nephrolithiasis (MONDO:0008171), neonatal ichthyosis-sclerosing cholangitis syndrome (MONDO:0011874), renal hypomagnesemia 5 with ocular involvement (MONDO:0009548)

Orphanet (3): Primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (Orphanet:31043), Neonatal ichthyosis-sclerosing cholangitis syndrome (Orphanet:59303), Primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement (Orphanet:2196)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000103	Polyuria
HP:0000121	Nephrocalcinosis
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000705	Amelogenesis imperfecta
HP:0000787	Nephrolithiasis
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001281	Tetany
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001941	Acidosis
HP:0001959	Polydipsia
HP:0002013	Vomiting
HP:0002027	Abdominal pain
HP:0002149	Hyperuricemia
HP:0002150	Hypercalciuria
HP:0002199	Hypocalcemic seizures
HP:0002748	Rickets
HP:0002857	Genu valgum
HP:0002901	Hypocalcemia
HP:0002905	Hyperphosphatemia

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D009397	Nephrocalcinosis	C12.050.351.968.419.590; C12.200.777.419.590; C12.950.419.590; C18.452.174.130.560
D053040	Nephrolithiasis	C12.050.351.968.419.600; C12.050.351.968.967.249; C12.200.777.419.600; C12.200.777.967.249; C12.950.419.600; C12.950.967.249
C537153	Hypomagnesemia primary (supp.)
C564365	Ichthyosis, Leukocyte Vacuoles, Alopecia, And Sclerosing Cholangitis (supp.)
C536148	Meier Blumberg Imahorn syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	3
Estradiol	affects cotreatment, decreases expression	2
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
mancozeb	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
polyhexamethyleneguanidine	affects expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	decreases expression	1
Ethanol	increases expression	1
Benzo(a)pyrene	decreases expression	1
Catechin	increases expression, affects cotreatment	1
Diethylnitrosamine	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	increases expression	1
Genistein	decreases expression	1

Clinical trials (associated diseases)

298 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00765128	PHASE4	COMPLETED	Intravenous Ketorolac for Postoperative Pain in Percutaneous Nephrolithotomy
NCT01295879	PHASE4	COMPLETED	Vitamin D Repletion in Stone Formers With Hypercalciuria
NCT01329042	PHASE4	COMPLETED	Efficacy of Potassium Sodium Hydrogen Citrate Therapy on Renal Stone Recurrence and/or Residual Fragments After Shockwave Lithotripsy and Percutaneous Nephrolithotomy in Calcium Oxalate Urolithiasis
NCT01452880	PHASE4	COMPLETED	Remifentanil in Extracorporeal Shock Wave Lithotripsy
NCT01675362	PHASE4	COMPLETED	Are There Protective Effects of Antioxidants, Calcium Channel Blocker and Angiotensin Receptor Blocker Against Extracorporeal Shockwaves Lithotripsy Induced Renal Injury?
NCT02011737	PHASE4	UNKNOWN	Naftopidil 75mg for Improving Clearance of Urinary Stones
NCT02095665	PHASE4	COMPLETED	Ureteral Stent-related Pain and Mirabegron (SPAM) Trial
NCT02375295	PHASE4	UNKNOWN	Struvite Stones Antibiotic Study
NCT02384200	PHASE4	COMPLETED	A Randomized Trial of Preoperative Prophylactic Antibiotics Prior to Kidney Stone Surgery (Percutaneous Nephrolithotomy [PCNL])
NCT02430168	PHASE4	UNKNOWN	Comparison of RIRS Versus PCNL Methods, According to Postoperative Pain and Analgesic Demand in 2 to 4 cm Renal Stones
NCT02430883	PHASE4	UNKNOWN	Is There Any Relation Between Pain and Stone Location in Retrograde Intrarenal Surgery?
NCT02443909	PHASE4	UNKNOWN	Comparison of Safety and Efficiency of 20w and 30w Holmium Laser Device in Management of 2-3 cm Diameter Kidney Stones With Retrograde Intrarenal Surgery
NCT02451319	PHASE4	UNKNOWN	Comparison of Safety and Efficiency of 20w 30w Holmium Laser Device in Treatment of 1-2 cm Diameter Kidney Stones With RIRS
NCT02489656	PHASE4	UNKNOWN	Quality of Life in Patients With Double Loop Ureteral Stent (JJ Silicone Hydrogel Study)
NCT02818140	PHASE4	COMPLETED	Ultrasound-guided Transmuscular Quadratus Lumborum Block for Percutaneous Nephrolithotomy
NCT02966236	PHASE4	UNKNOWN	Impact of Tranexamic Acid Use in Percutaneous Nephrolithotomy
NCT03035812	PHASE4	COMPLETED	Alkalinization by Urologists & Nephrologists
NCT03229889	PHASE4	COMPLETED	Trial of Tadalafil, Tamsulosin and Combination for Access Sheath Deployment
NCT03332056	PHASE4	COMPLETED	The Use of Belladonna and Opium Suppository in the Treatment of Postoperative Stent Pain
NCT03549611	PHASE4	WITHDRAWN	Pre-induction Analgesia: Multimodel Regimen vs Aceteminophen for Post Ureteroscopy Pain
NCT03692715	PHASE4	COMPLETED	Antibiotic Prophylaxis Before Shock Wave Lithotripsy
NCT03872843	PHASE4	COMPLETED	Opioid Free Management After Ureteroscopy
NCT03888144	PHASE4	COMPLETED	Study of Ketorolac Versus Opioid for Pain After Endoscopy
NCT04095975	PHASE4	COMPLETED	Effectiveness of Urinary Alkalinizing Agents on Kidney Stone Risk
NCT04663269	PHASE4	TERMINATED	Regional Erector Spinae Analgesic Block vs Standard of Care Undergoing Percutaneous Nephrolithotomy
NCT05082142	PHASE4	COMPLETED	Tranexamic Acid to Improve Same-day Discharge Rates After Holmium Laser Enucleation of the Prostate (HoLEP)
NCT05365477	PHASE4	COMPLETED	Empiric Versus Selective Prevention Strategies for Kidney Stone Disease
NCT05414669	PHASE4	COMPLETED	Allopurinol Effect on MDA,NO,KIM-1 Urine Levels, RI and Renal Elastography in Kidney Stone Patients Post ESWL
NCT05924165	PHASE4	COMPLETED	Narcotic-Free Percutaneous Nephrolithotomy
NCT06124066	PHASE4	COMPLETED	THE EFFECTS OF MIRABEGRON AND TAMSULOSIN FOR PATIENTS WITH URETERAL STENTS
NCT06966635	PHASE4	RECRUITING	Exploratory Study on the Treatment of Gout With Potassium Citrate Sustained-release Tablets
NCT07124299	PHASE4	RECRUITING	Alpha-Blockers Prior to Ureteral Access Sheath Placement in Flexible Ureteroscopy: A Randomized Prospective Study
NCT07225764	PHASE4	RECRUITING	CaOx Stone Prevention
NCT07512297	PHASE4	NOT_YET_RECRUITING	Pain Control During ESWL Using Non-Opioid Analgesics
NCT07582341	PHASE4	COMPLETED	Combined Intravenous and Irrigation Tranexamic Acid During Percutaneous Nephrolithotomy
NCT00249951	PHASE3	COMPLETED	Alkaline Citrate Treatment to Lower the Risk of Nephrocalcinosis in Preterm Infants
NCT01756547	PHASE3	UNKNOWN	Study to Assess the Efficacy and Safety of Oral Potassium Citrate on the Prevention of Nephrocalcinosis in Extreme Premature
NCT00004284	PHASE3	COMPLETED	Phase III Randomized, Double-Blind Study of Potassium Phosphate Vs Potassium Citrate for Absorptive Hypercalciuria
NCT00177086	PHASE3	COMPLETED	Alfuzosin Hydrochloride to Promote Passage of Distal Ureteral Calculi
NCT00713739	PHASE3	UNKNOWN	Alfuzosin for Medical Expulsion Therapy of Ureteral Stones