SLC12A3

Summary

SLC12A3 (solute carrier family 12 member 3, HGNC:10912) is a protein-coding gene on chromosome 16q13, encoding Solute carrier family 12 member 3 (P55017). Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules.

This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter’s syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6559 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Gitelman syndrome (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 1,999 total — 197 pathogenic, 173 likely-pathogenic
• Phenotypes (HPO): 85
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001126108

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10912
Approved symbol	SLC12A3
Name	solute carrier family 12 member 3
Location	16q13
Locus type	gene with protein product
Status	Approved
Aliases	NCCT, NCC, TSC
Ensembl gene	ENSG00000070915
Ensembl biotype	protein_coding
OMIM	600968
Entrez	6559

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 25 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000262502, ENST00000438926, ENST00000563236, ENST00000563352, ENST00000566786, ENST00000569002, ENST00000898207, ENST00000898208, ENST00000898209, ENST00000898210, ENST00000898211, ENST00000898212, ENST00000898213, ENST00000898214, ENST00000898215, ENST00000898216, ENST00000898217, ENST00000898218, ENST00000898219, ENST00000898220, ENST00000898221, ENST00000898222, ENST00000898223, ENST00000898224, ENST00000898225, ENST00000898226, ENST00000898227

RefSeq mRNA: 4 — MANE Select: NM_001126108 NM_000339, NM_001126107, NM_001126108, NM_001410896

CCDS: CCDS10770, CCDS45491, CCDS58464, CCDS92165

Canonical transcript exons

ENST00000563236 — 26 exons

Exon	Start	End
ENSE00000335892	56869729	56869824
ENSE00000335893	56870096	56870235
ENSE00000335895	56872351	56872462
ENSE00000336020	56884049	56884204
ENSE00000336027	56892953	56893054
ENSE00000684699	56867070	56867216
ENSE00000684718	56868297	56868372
ENSE00000684722	56870626	56870736
ENSE00000684727	56879073	56879227
ENSE00000684728	56879542	56879649
ENSE00000684729	56880130	56880253
ENSE00000684733	56885265	56885364
ENSE00000684734	56886364	56886475
ENSE00000684741	56886953	56887093
ENSE00000684743	56887925	56888031
ENSE00000684744	56890274	56890356
ENSE00000684747	56894531	56894642
ENSE00000684748	56899530	56899616
ENSE00000684750	56902373	56902508
ENSE00000684778	56904395	56904462
ENSE00000852836	56872656	56872786
ENSE00000852837	56882396	56882497
ENSE00001166274	56878077	56878161
ENSE00002590899	56892083	56892133
ENSE00003902561	56865207	56865517
ENSE00003904150	56913264	56915850

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 92.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4751 / max 256.6514, expressed in 62 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154288	1.0337	47
154287	0.4414	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adult mammalian kidney	UBERON:0000082	92.59	gold quality
nephron tubule	UBERON:0001231	85.23	gold quality
kidney	UBERON:0002113	85.03	gold quality
kidney epithelium	UBERON:0004819	81.36	silver quality
buccal mucosa cell	CL:0002336	80.81	gold quality
metanephros cortex	UBERON:0010533	79.46	gold quality
renal glomerulus	UBERON:0000074	77.71	silver quality
cortex of kidney	UBERON:0001225	77.39	gold quality
metanephros	UBERON:0000081	73.45	gold quality
renal medulla	UBERON:0000362	65.03	gold quality
pancreatic ductal cell	CL:0002079	64.81	silver quality
tibialis anterior	UBERON:0001385	62.82	silver quality
ileal mucosa	UBERON:0000331	62.47	silver quality
granulocyte	CL:0000094	62.20	gold quality
lymph node	UBERON:0000029	61.61	gold quality
deltoid	UBERON:0001476	59.28	silver quality
leukocyte	CL:0000738	59.09	gold quality
mononuclear cell	CL:0000842	58.72	gold quality
spleen	UBERON:0002106	58.60	gold quality
monocyte	CL:0000576	58.57	gold quality
adult organism	UBERON:0007023	57.77	gold quality
decidua	UBERON:0002450	56.55	gold quality
upper leg skin	UBERON:0004262	56.27	gold quality
bone marrow cell	CL:0002092	55.67	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	55.41	gold quality
vermiform appendix	UBERON:0001154	55.18	gold quality
biceps brachii	UBERON:0001507	54.04	gold quality
quadriceps femoris	UBERON:0001377	54.00	gold quality
skin of hip	UBERON:0001554	53.12	silver quality
caecum	UBERON:0001153	53.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	10439.24
E-GEOD-131882	yes	8010.48
E-CURD-135	yes	5829.64
E-ANND-3	yes	4.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting SLC12A3, 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-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Interaction with grp58 increases activity of the thiazide-sensitive Na-Cl cotransporter. (PMID:11832422)
• gene mutation associated with hypokalemic salt-losing tubulopathies. (PMID:11893344)
• Novel thiazide-sensitive Na-Cl cotransporter mutation in a Chinese patient with Gitelman’s syndrome presenting as hypokalaemic paralysis. (PMID:12686679)
• Diabetic patients at >55,000 SNP loci indicated a gene encoding solute carrier family 12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy (PMID:14578305)
• 7 different mutations of the NCCT gene were identified consisting of 3 missense, 1 splice site, and 3 silent mutations. Four of these mutations were novel. (PMID:14655226)
• novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. (PMID:14675033)
• the G264A polymorphism is associated with reduction in the substrate translocation rate of the cotransporter, due to a decrease in the intrinsic activity (PMID:14766743)
• Human site directed mutagenesis is associated with Gitelman Syndrome in mice. (PMID:15102966)
• G2736A polymorphism of the TSC gene is a genetic predisposing factor for essential hypertension in Japanese women. (PMID:15480096)
• SLC12A3 +78A(+) genotype may have a protective effect against the development and/or progression of diabetic nephropathy in Japanese type 2 diabetic patients. (PMID:15915338)
• Patient with Gitelman syndrome is due to a mutation of the SLC123A gene. (PMID:16221718)
• data suggest that WNK4 wild type significantly inhibits sodium chloride cotransporter (NCC) surface expression, not owing to an increase in clathrin-mediated endocytosis of NCC, but likely from enhanced degradation of NCC through a lysosomal pathway (PMID:16688122)
• NCC is activated by a mechanism that involves amino-terminal domain phosphorylation (PMID:16887815)
• 13 different causative mutations in a cohort of Gitelman syndrome patients (PMID:17159356)
• data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of Gitelman syndrome and provide new insights in the underlying pathogenic mechanisms of the disease (PMID:17329572)
• Novel mutations in the SLC12A3 gene causing Gitelman’s syndrome in Swedes. (PMID:17654016)
• Two sporadic cases of Gitelman’s syndrome and two novel genotypes of SLC12A3. (PMID:17873326)
• substitution of arginine for cysteine at position 919 increases Na transport function and supports the hypothesis that mutations in renal tubular Na transporters contribute to the development of primary hypertension by increasing renal Na reabsorption (PMID:17885550)
• No relation was found between sodium-chloride cotransporter expression and type of mutation in the SLC12A3 gene was found in patients with Gitelman syndrome. (PMID:17954289)
• Results report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes. (PMID:17975670)
• Gitelmans syndrome heterozygotes are partially protected from hypertension through partial genetic loss of function of the NCCT. (PMID:17981812)
• roles of Thr418Ser polymorphism of the CLCNKB gene and Arg904Gln polymorphism in the TSC gene on essential hypertension need to be explored in other ethnic groups (PMID:17997379)
• Genetic variation at the SLC12A3 locus is unlikely to explain the risk for advanced diabetic nephropathy among type 2 diabetic Caucasians. (PMID:18263927)
• The WNK1-SPAK/OSR1 signalling pathway plays a key role in controlling the phosphorylation and activity of NCC. (PMID:18270262)
• Thr60Met may be the most common mutation in Chinese patients with GS. Possible specific genotype-phenotype correlations were difficult to identify. (PMID:18287808)
• The causal gene of Gitelman’s syndrome (SLC12A3) is not involved in determining blood pressure levels. (PMID:18362449)
• Members of the Framingham Heart Study were screened for variation in three genes-SLC12A3, SLC12A1 and KCNJ1 causing rare recessive diseases featuring large reductions in blood pressure. (PMID:18391953)
• sequencing of PVALB was performed in 132 cases of Gitelman’s syndrome in whom only one or no (N = 79) mutant SLC12A3 allele was found (PMID:18469313)
• analysis of a novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney [case report] (PMID:18580052)
• 13 variants, including five novel variants in the SLC12A3 gene in 13 patients with Gitelman syndrome. (PMID:19207868)
• homozygosity for this mutation resulted in a significant loss of normal SLC12A3 transcript (PMID:19420906)
• 9 novel SLC12A3 gene variants, including seven missense mutations, one splice mutation, and one frameshift deletion, were found in 12 subjectsiwth Gitelman’s syndrome and aldosteronism. (PMID:19451210)
• analysis of how a deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome [case report] (PMID:19668106)
• WNK4 promotes sodium chloride co-transporter targeting to the lysosome for degradation via a mechanism involving sortilin. (PMID:19875813)
• likely that the c.1196_1202dup7bp mutation in the SLC12A3 gene reflects the presence of a common ancestor in Gitelman syndrome an area covering the northern-central part of Italy and eastern France. (PMID:20675610)
• Deep intronic mutations in SLC12A3 causing defective transporter expression can be identified in Gitelman’s syndrome. (PMID:21051746)
• Mutation leads to a failure of the thiazide-sensitive sodium-2-chloride-cotransporter, the so called Gitelman syndrome, which presents similar to a chronic thiazide therapy (PMID:21161146)
• gamma-adducin may influence blood pressure homeostasis by modulating renal NaCl transport. (PMID:21164023)
• Data show that K1169E lost its inhibitory effect on NCC surface expression compared to wild-type WNK4 when expressed in HEK293 cells, while it did not change NCC total protein expression. (PMID:21196779)
• Missense mutations account for approximately 59% of the mutations in Gitelman’s syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene. (PMID:21415153)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc12a3	ENSDARG00000013855
mus_musculus	Slc12a3	ENSMUSG00000031766
rattus_norvegicus	Slc12a3	ENSRNOG00000057072
drosophila_melanogaster	CG10413	FBGN0032689
drosophila_melanogaster	Ncc69	FBGN0036279
drosophila_melanogaster	kcc	FBGN0261794
caenorhabditis_elegans		WBGENE00012543
caenorhabditis_elegans		WBGENE00019205
caenorhabditis_elegans		WBGENE00020207

Paralogs (8): SLC12A2 (ENSG00000064651), SLC12A1 (ENSG00000074803), SLC12A7 (ENSG00000113504), SLC12A4 (ENSG00000124067), SLC12A5 (ENSG00000124140), SLC12A6 (ENSG00000140199), SLC12A9 (ENSG00000146828), SLC12A8 (ENSG00000221955)

Protein

Protein identifiers

Solute carrier family 12 member 3 — P55017 (reviewed: P55017)

Alternative names: Na-Cl cotransporter, Na-Cl symporter, Thiazide-sensitive sodium-chloride cotransporter

All UniProt accessions (2): P55017, J3QSS1

UniProt curated annotations — full annotation on UniProt →

Function. Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules. Also acts as a receptor for the pro-inflammatory cytokine IL18, thereby contributing to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1.

Subunit / interactions. Homodimer; adopts a domain-swap conformation at the scissor helices connecting the transmembrane domain and C-terminal domain. Interacts with KLHL3. Interacts with IL18R1; this interaction is increased by IL18 treatment.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Predominantly expressed in the kidney (at protein level). Localizes to the distal convoluted tubules (at protein level). Not detected in normal aorta, but abundantly expressed in fatty streaks and advanced atherosclerotic lesions (at protein level).

Post-translational modifications. Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3. However, it was later shown that it is not the case. Phosphorylated at Thr-46, Thr-55, Thr-60 and Ser-91 by OXSR1/OSR1 and STK39/SPAK downstream of WNK4, promoting its activity. Phosphorylated in response to IL18.

Disease relevance. Gitelman syndrome (GTLMNS) [MIM:263800] An autosomal recessive disorder characterized by hypokalemic alkalosis in combination with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. Patients are often asymptomatic or present transient periods of muscular weakness and tetany, usually accompanied by abdominal pain, vomiting and fever. The phenotype is highly heterogeneous in terms of age at onset and severity. Cardinal features such as hypocalciuria and hypomagnesemia might also change during the life cycle of a given patient. It has overlapping features with Bartter syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Phosphorylation by OXSR1/OSR1 and STK39/SPAK in kidney distal convoluted tubules downstream of WNK4 promotes its activity. Also activated by OXSR1/OSR1 and STK39/SPAK downstream of WNK3. Target of thiazide diuretics used in the treatment of high blood pressure. Thiazide drugs, such as polythiazide, specifically inhibit SLC12A3/NCC transporter activity by competing with chloride for binding and by locking SLC12A3/NCC in an outward-facing conformation.

Domain organisation. Interaction between the cytoplasmic N-terminal and C-terminal domains (NTD and CTD, respectively) is essential for SLC12A3/NCC transporter activity. Phosphorylation by OXSR1/OSR1 and STK39/SPAK may activate SLC12A3/NCC by facilitating this interaction.

Similarity. Belongs to the SLC12A transporter family.

Isoforms (3)

UniProt ID	Names	Canonical?
P55017-1	1	yes
P55017-2	2
P55017-3	3

RefSeq proteins (4): NP_000330, NP_001119579, NP_001119580, NP_001397825 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002948	SLC12A3	Family
IPR004841	AA-permease/SLC12A_dom	Domain
IPR004842	SLC12A_fam	Family
IPR013612	AA_permease_N	Domain
IPR018491	SLC12_C	Domain

Pfam: PF00324, PF03522, PF08403

Catalyzed reactions (Rhea), 1 shown:

• chloride(out) + Na(+)(out) = chloride(in) + Na(+)(in) (RHEA:73887)

UniProt features (295 total): sequence variant 132, helix 46, mutagenesis site 24, binding site 20, strand 18, transmembrane region 12, turn 11, topological domain 10, modified residue 10, sequence conflict 4, glycosylation site 2, disulfide bond 2, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9PIG	ELECTRON MICROSCOPY	2.79
8FHQ	ELECTRON MICROSCOPY	2.81
7Y6I	ELECTRON MICROSCOPY	2.85
8FHR	ELECTRON MICROSCOPY	2.9
8FHO	ELECTRON MICROSCOPY	2.95
8FHN	ELECTRON MICROSCOPY	3
9PIE	ELECTRON MICROSCOPY	3.01
8FHT	ELECTRON MICROSCOPY	3.02
8FHP	ELECTRON MICROSCOPY	3.04
9PIF	ELECTRON MICROSCOPY	3.24
7YG0	ELECTRON MICROSCOPY	3.75
7YG1	ELECTRON MICROSCOPY	3.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55017-F1	80.94	0.46

Functional residue map

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

Ligand- & substrate-binding residues (20): 148; 149; 151; 227; 234; 352; 353; 354; 355; 359; 464; 467 …

Post-translational modifications (10): 43, 46, 49, 50, 55, 60, 73, 91, 124, 126

Disulfide bonds (2): 416–421, 430–436

Glycosylation sites (2): 406, 426

Mutagenesis-validated functional residues (24):

Position	Phenotype
19	abolished interaction with oxsr1/osr1 and stk39/spak, preventing phosphorylation and activation.
46	decreased phosphorylation by oxsr1/osr1 and stk39/spak.
55	decreased phosphorylation by oxsr1/osr1 and stk39/spak.
60	decreased phosphorylation by oxsr1/osr1 and stk39/spak.
62	abolished sodium and chloride ion cotransporter activity.
70	abolished sodium and chloride ion cotransporter activity.
83	abolished sodium and chloride ion cotransporter activity.
86	abolished sodium and chloride ion cotransporter activity.
91	decreased phosphorylation by oxsr1/osr1 and stk39/spak.
149	reduced sensitivity to thiazide diuretics. reduced sodium and chloride ion cotransporter activity.
158	strongly reduced sodium and chloride ion cotransporter activity.
223	reduced sensitivity to thiazide diuretics.
227	strongly reduced sodium and chloride ion cotransporter activity.
234	strongly reduced sodium and chloride ion cotransporter activity.
240	strongly reduced sodium and chloride ion cotransporter activity.
386	strongly reduced sodium and chloride ion cotransporter activity.
467	abolished sodium and chloride ion cotransporter activity.
468	abolished sodium and chloride ion cotransporter activity.
526	strongly reduced sodium and chloride ion cotransporter activity.
540	abolished sodium and chloride ion cotransporter activity.
765	reduced sodium and chloride ion cotransporter activity.
838	abolished sodium and chloride ion cotransporter activity.
886	reduced sodium and chloride ion cotransporter activity.
1009	abolished sodium and chloride ion cotransporter activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-426117	Cation-coupled Chloride cotransporters
R-HSA-5619087	Defective SLC12A3 causes Gitelman syndrome (GS)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 329 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, MODULE_162, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, SHEPARD_CRASH_AND_BURN_MUTANT_UP, MODULE_64, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GNF2_ANK1, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, MODULE_368, GOBP_CHLORIDE_TRANSPORT, GOBP_RESPONSE_TO_KETONE, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (13): monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), cell volume homeostasis (GO:0006884), sodium ion transmembrane transport (GO:0035725), chloride ion homeostasis (GO:0055064), potassium ion homeostasis (GO:0055075), sodium ion homeostasis (GO:0055078), renal sodium ion absorption (GO:0070294), response to salt (GO:1902074), chloride transmembrane transport (GO:1902476), response to aldosterone (GO:1904044), potassium ion import across plasma membrane (GO:1990573), transmembrane transport (GO:0055085)

GO Molecular Function (9): ATP binding (GO:0005524), sodium:potassium:chloride symporter activity (GO:0008511), sodium:chloride symporter activity (GO:0015378), nucleotide binding (GO:0000166), protein binding (GO:0005515), sodium ion transmembrane transporter activity (GO:0015081), symporter activity (GO:0015293), chloride:monoatomic cation symporter activity (GO:0015377), transmembrane transporter activity (GO:0022857)

GO Cellular Component (5): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC-mediated transport of inorganic anions	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	3
transport	2
monoatomic cation homeostasis	2
cellular anatomical structure	2
metal ion transport	1
regulation of cell size	1
cellular homeostasis	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic anion homeostasis	1
renal sodium ion transport	1
renal absorption	1
response to chemical	1
chloride transport	1
monoatomic anion transmembrane transport	1
response to mineralocorticoid	1
response to alcohol	1
response to ketone	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
cellular process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
potassium:sodium symporter activity	1
sodium:chloride symporter activity	1
potassium:chloride symporter activity	1
monoatomic anion:sodium symporter activity	1
chloride:monoatomic cation symporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
sodium ion transmembrane transport	1
metal ion transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
chloride transmembrane transporter activity	1
monoatomic anion:monoatomic cation symporter activity	1
transporter activity	1
transmembrane transport	1
cytoplasm	1
membrane	1

Protein interactions and networks

STRING

1274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC12A3	WNK4	Q96J92	966
SLC12A3	KCNJ1	P48048	959
SLC12A3	CLCNKB	P51801	958
SLC12A3	WNK1	P54963	948
SLC12A3	WNK3	Q9BYP7	909
SLC12A3	STK39	Q9UEW8	904
SLC12A3	BSND	Q8WZ55	895
SLC12A3	CLDN16	Q9Y5I7	874
SLC12A3	CLCNKA	P51800	872
SLC12A3	SCNN1A	P37088	857
SLC12A3	OXSR1	O95747	856
SLC12A3	REN	P00797	836
SLC12A3	FXYD2	P54710	828
SLC12A3	SCNN1B	P51168	815
SLC12A3	SCNN1G	P51170	801

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SLC12A3	Klhl3	psi-mi:“MI:0915”(physical association)	0.400
	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
SLC12A3	SNX2	psi-mi:“MI:0914”(association)	0.350
SLC12A3	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): SLC12A3 (Affinity Capture-MS), SLC12A3 (Affinity Capture-MS), SLC12A3 (Affinity Capture-MS), PDIA3 (Two-hybrid), SLC12A3 (Affinity Capture-RNA), SNX5 (Affinity Capture-MS), SNX2 (Affinity Capture-MS), GUCY1B3 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), SNX6 (Affinity Capture-MS), SNX1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), ABCA3 (Affinity Capture-MS), AIP (Affinity Capture-MS), BAG2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KTI4, A0A0J9UR41, A2QHC2, A2QNG6, A2R0Z5, E9E1W3, E9EDR6, E9EE69, F1Q749, G2WY98, G2XEK6, G4MVT6, G4N1B2, H6C2T9, H6C4I7, I1S097, I1S0T9, O48538, P29070, P30583, P30588, P30601, P30602, P31596, P32481, P43004, P43006, P49283, P54267, P55011, P55012, P55013, P55014, P55015, P55016, P55017, P55018, P58421, P59158, Q12564

Diamond homologs: A0A0G2KTI4, A0AV02, A2BFP5, P38329, P55011, P55012, P55013, P55014, P55015, P55016, P55017, P55018, P55019, P59158, Q13621, Q25479, Q6A4L1, Q8CJI3, Q8VI23, Q9BXP2, O60146, Q2UVJ5, Q657W3, Q66HR0, Q99MR3, Q0VGW6, Q6Z0E2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
OXSR1	up-regulates	SLC12A3	phosphorylation
STK39	“down-regulates activity”	SLC12A3	phosphorylation
WNK3	“up-regulates activity”	SLC12A3	phosphorylation
WNK4	“up-regulates activity”	SLC12A3	phosphorylation
WNK4	“down-regulates activity”	SLC12A3
SLC12A3	“up-regulates quantity”	chloride	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1999 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	197
Likely pathogenic	173
Uncertain significance	480
Likely benign	807
Benign	109

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101514	NM_001126108.2(SLC12A3):c.179C>T (p.Thr60Met)	Pathogenic
1067670	NM_001126108.2(SLC12A3):c.2856+2T>A	Pathogenic
1069000	NC_000016.9:g.(?56921827)(56921953_?)del	Pathogenic
1069508	NM_001126108.2(SLC12A3):c.911C>T (p.Thr304Met)	Pathogenic
1071753	NM_001126108.2(SLC12A3):c.2239C>T (p.Gln747Ter)	Pathogenic
1071754	NM_001126108.2(SLC12A3):c.2379dup (p.Phe794fs)	Pathogenic
1073480	NM_001126108.2(SLC12A3):c.1930del (p.Gln644fs)	Pathogenic
1075065	NC_000016.9:g.(?56925985)(56936430_?)del	Pathogenic
1075066	NC_000016.9:g.(?56906253)(56912083_?)del	Pathogenic
1075402	NM_001126108.2(SLC12A3):c.334G>T (p.Glu112Ter)	Pathogenic
1075403	NM_001126108.2(SLC12A3):c.2504G>A (p.Trp835Ter)	Pathogenic
1075648	NM_001126108.2(SLC12A3):c.2866C>T (p.Gln956Ter)	Pathogenic
1075650	NM_001126108.2(SLC12A3):c.2924+1G>A	Pathogenic
1076125	NM_001126108.2(SLC12A3):c.2544T>G (p.Tyr848Ter)	Pathogenic
1076695	NM_001126108.2(SLC12A3):c.569C>A (p.Ser190Ter)	Pathogenic
1172519	NM_001126108.2(SLC12A3):c.659del (p.Gly220fs)	Pathogenic
1301841	NM_001126108.2(SLC12A3):c.2800_2803del (p.Arg934fs)	Pathogenic
1367232	NM_000339.2(SLC12A3):c.2039delG	Pathogenic
1373755	NM_001126108.2(SLC12A3):c.2856+1G>A	Pathogenic
1376757	NM_001126108.2(SLC12A3):c.1047del (p.Ser350fs)	Pathogenic
1382757	NM_001126108.2(SLC12A3):c.964+1G>A	Pathogenic
1393514	NM_001126108.2(SLC12A3):c.2143G>T (p.Glu715Ter)	Pathogenic
1393569	NM_001126108.2(SLC12A3):c.1568-1G>A	Pathogenic
1397263	NM_001126108.2(SLC12A3):c.2717_2720dup (p.His907fs)	Pathogenic
1403834	NM_001126108.2(SLC12A3):c.293_296dup (p.His99fs)	Pathogenic
1412538	NM_001126108.2(SLC12A3):c.1238G>A (p.Trp413Ter)	Pathogenic
1443034	NM_001126108.2(SLC12A3):c.2420T>A (p.Val807Glu)	Pathogenic
1446379	NM_001126108.2(SLC12A3):c.2521+253C>T	Pathogenic
1451792	NM_001126108.2(SLC12A3):c.1807del (p.Val603fs)	Pathogenic
1452356	NC_000016.9:g.(?56911979)(56918126_?)dup	Pathogenic

SpliceAI

4366 predictions. Top by Δscore:

Variant	Effect	Δscore
16:56865515:AAGGT:A	donor_loss	1.0000
16:56865516:AG:A	donor_gain	1.0000
16:56865516:AGGT:A	donor_loss	1.0000
16:56865517:GG:G	donor_gain	1.0000
16:56865518:G:GA	donor_loss	1.0000
16:56865518:G:GG	donor_gain	1.0000
16:56867208:G:GT	donor_gain	1.0000
16:56868370:TCGG:T	donor_loss	1.0000
16:56868371:CGGTG:C	donor_loss	1.0000
16:56868373:G:GG	donor_gain	1.0000
16:56868373:GT:G	donor_loss	1.0000
16:56868374:T:TC	donor_loss	1.0000
16:56868375:G:GT	donor_loss	1.0000
16:56869727:A:AG	acceptor_gain	1.0000
16:56869728:G:GG	acceptor_gain	1.0000
16:56870071:AT:A	acceptor_gain	1.0000
16:56870233:CAG:C	donor_loss	1.0000
16:56870235:GGT:G	donor_loss	1.0000
16:56870236:GTG:G	donor_loss	1.0000
16:56870237:T:A	donor_loss	1.0000
16:56870621:CCCA:C	acceptor_loss	1.0000
16:56870623:CA:C	acceptor_loss	1.0000
16:56870624:A:AC	acceptor_loss	1.0000
16:56870624:A:AG	acceptor_gain	1.0000
16:56870625:G:GG	acceptor_gain	1.0000
16:56870625:GGA:G	acceptor_gain	1.0000
16:56870625:GGAGT:G	acceptor_gain	1.0000
16:56870734:AAGG:A	donor_loss	1.0000
16:56870735:AGGT:A	donor_loss	1.0000
16:56870738:T:G	donor_loss	1.0000

AlphaMissense

6716 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:56870152:G:C	G220R	1.000
16:56870153:G:A	G220D	1.000
16:56872749:G:A	G353D	1.000
16:56872760:G:T	G357W	1.000
16:56869795:C:A	A191D	0.999
16:56869808:T:A	N195K	0.999
16:56869808:T:G	N195K	0.999
16:56870111:T:C	L206P	0.999
16:56870120:G:C	R209P	0.999
16:56870122:A:C	S210R	0.999
16:56870124:T:A	S210R	0.999
16:56870124:T:G	S210R	0.999
16:56870128:G:C	G212R	0.999
16:56870129:G:A	G212D	0.999
16:56870140:G:T	G216W	0.999
16:56872748:G:C	G353R	0.999
16:56872760:G:A	G357R	0.999
16:56872760:G:C	G357R	0.999
16:56872761:G:A	G357E	0.999
16:56872782:T:A	L364H	0.999
16:56872782:T:C	L364P	0.999
16:56878101:G:A	G374R	0.999
16:56878101:G:C	G374R	0.999
16:56878101:G:T	G374W	0.999
16:56878102:G:A	G374E	0.999
16:56880134:T:C	L483P	0.999
16:56882438:T:A	L537H	0.999
16:56882438:T:C	L537P	0.999
16:56882460:C:A	N544K	0.999
16:56882460:C:G	N544K	0.999

dbSNP variants (sampled 300 via entrez): RS1000030183 (16:56898666 C>A,T), RS1000162531 (16:56888620 G>A), RS1000170021 (16:56881383 C>T), RS1000217074 (16:56888289 G>A), RS1000321637 (16:56893584 A>C), RS1000327040 (16:56869005 A>G), RS1000330343 (16:56903754 C>G,T), RS1000421640 (16:56893370 C>T), RS1000570303 (16:56878663 G>A), RS1000739702 (16:56908277 C>G), RS1000772161 (16:56907906 C>G), RS1000923405 (16:56867702 G>A), RS1000937023 (16:56902676 G>A,C), RS1001037813 (16:56897690 G>A), RS1001284121 (16:56915415 G>A)

Disease associations

OMIM: gene MIM:600968 | disease phenotypes: MIM:263800, MIM:601678

GenCC curated gene-disease

Disease	Classification	Inheritance
Gitelman syndrome	Strong	Autosomal recessive

Mondo (5): Gitelman syndrome (MONDO:0009904), Bartter syndrome (MONDO:0015231), inherited renal tubular disease (MONDO:0015962), renal tubular acidosis (MONDO:0001909), congenital portosystemic shunt (MONDO:0018811)

Orphanet (4): Gitelman syndrome (Orphanet:358), Bartter syndrome (Orphanet:112), Genetic renal tubular disease (Orphanet:183592), Congenital portosystemic shunt (Orphanet:480531)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000020	Urinary incontinence
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000103	Polyuria
HP:0000128	Renal potassium wasting
HP:0000360	Tinnitus
HP:0000622	Blurred vision
HP:0000805	Enuresis
HP:0000823	Delayed puberty
HP:0000848	Increased circulating renin concentration
HP:0000855	Insulin resistance
HP:0000872	Hashimoto thyroiditis
HP:0000934	Chondrocalcinosis
HP:0000975	Hyperhidrosis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001262	Excessive daytime somnolence
HP:0001279	Syncope
HP:0001281	Tetany
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001657	Prolonged QT interval
HP:0001663	Ventricular fibrillation
HP:0001698	Pericardial effusion
HP:0001891	Iron deficiency anemia
HP:0001947	Renal tubular acidosis
HP:0001949	Hypokalemic alkalosis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000331_1	HDL cholesterol	4.000000e-93
GCST001904_2	HDL cholesterol	1.000000e-24
GCST003363_2	HDL cholesterol levels	1.000000e-16
GCST007465_14	Phoneme awareness	5.000000e-07
GCST011927_5	HDL levels x fish oil supplementation interaction (2df)	5.000000e-91
GCST011930_1	HDL levels x fish oil supplementation interaction (1df)	2.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005301	reading and spelling ability
EFO:0600007	fish oil supplement exposure measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000141	Acidosis, Renal Tubular	C12.050.351.968.419.815.093; C12.200.777.419.815.093; C12.950.419.815.093; C16.320.831.093; C18.452.076.176.210
D001477	Bartter Syndrome	C12.050.351.968.419.815.279; C12.200.777.419.815.279; C12.950.419.815.279; C19.053.800.604.249
D053579	Gitelman Syndrome	C12.050.351.968.419.815.491; C12.200.777.419.815.491; C12.950.419.815.491; C16.320.831.491

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1876 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13306673	Efficacy	3	Thiazides;plain	Essential hypertension
rs1529927	Efficacy	3	bumetanide;furosemide;torasemide

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1529927	SLC12A3	3	4.00	1	bumetanide;furosemide;torasemide
rs13306673	SLC12A3	3	2.25	1	Thiazides;plain

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC12 family of cation-coupled chloride transporters

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	increases expression, increases methylation, affects cotreatment	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sulforaphane	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Succimer	affects cotreatment, decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Urethane	decreases expression	1
Zidovudine	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Magnetite Nanoparticles	affects cotreatment, decreases expression	1
Coal Ash	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5209622	Functional	Substrate uptake by the thiazide-sensitive electroneutral NaCl co-transporter (NCC, SLC12A3) as assessed by a Cl- sensitive FRET (Fluorescence Resonance Energy Transfer) sensor (SuperClomeleon) in HEK-293 JumpIN-SLC12A3 cells (PubChem AID:	Superclomeleon biosensor based assay for SLC12A3 using HEK-293 SLC12A3 OE cells

Cellosaurus cell lines

4 cell lines: 2 induced pluripotent stem cell, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2GD	CMCi002-A	Induced pluripotent stem cell	Male
CVCL_A5GL	WMUi021-A	Induced pluripotent stem cell	Male
CVCL_D4DH	HEK-SLC12A3-KO-c7	Transformed cell line	Female
CVCL_D4DI	HEK-SLC12A3-KO-c8	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02297048	PHASE4	COMPLETED	Monocentric STUDY, Randomised Double Blinded (Healthy Subjects, or Transversal (Patients With Gitelman Syndrome)
NCT01146197	PHASE1/PHASE2	COMPLETED	Input of the Use of Indometacin in Gitelman Syndrome as Compared to Potassium Sparing Diuretics
NCT00822107	Not specified	COMPLETED	A Translational Approach to Gitelman Syndrome
NCT04995627	Not specified	COMPLETED	Salt Supplementation in Gitelman Syndrome
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06922370	Not specified	RECRUITING	The Osteoarticular Manifestations in Patients With Gitelman Syndrome
NCT03847571	Not specified	UNKNOWN	Acetazolamide (AZ) for Management of Alkalosis in Bartter Syndrome
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension