SLC12A1

Summary

SLC12A1 (solute carrier family 12 member 1, HGNC:10910) is a protein-coding gene on chromosome 15q21.1, encoding Solute carrier family 12 member 1 (Q13621). Renal sodium, potassium and chloride non-electrogenic ion symporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation.

This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle’s loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.

Source: NCBI Gene 6557 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete antenatal Bartter syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,062 total — 53 pathogenic, 55 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000338

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10910
Approved symbol	SLC12A1
Name	solute carrier family 12 member 1
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	NKCC2, CCC2, BSC1, BSC, BSC-1
Ensembl gene	ENSG00000074803
Ensembl biotype	protein_coding
OMIM	600839
Entrez	6557

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000330289, ENST00000380993, ENST00000396577, ENST00000558252, ENST00000558805, ENST00000559641, ENST00000559723, ENST00000560692, ENST00000561031, ENST00000561127, ENST00000646012, ENST00000647232, ENST00000647546, ENST00000686073

RefSeq mRNA: 3 — MANE Select: NM_000338 NM_000338, NM_001184832, NM_001384136

CCDS: CCDS10129, CCDS53940, CCDS91995

Canonical transcript exons

ENST00000380993 — 27 exons

Exon	Start	End
ENSE00001857249	48206302	48206330
ENSE00003471534	48232727	48232838
ENSE00003474193	48288405	48288516
ENSE00003477119	48269658	48269764
ENSE00003484858	48244753	48244904
ENSE00003498067	48301315	48301382
ENSE00003502971	48229189	48229328
ENSE00003509782	48299140	48299275
ENSE00003525912	48267561	48267701
ENSE00003544875	48241515	48241599
ENSE00003551709	48247337	48247460
ENSE00003562055	48291778	48291864
ENSE00003564590	48230393	48230503
ENSE00003572383	48234877	48235004
ENSE00003576916	48220921	48220996
ENSE00003585509	48274571	48274653
ENSE00003586397	48251615	48251770
ENSE00003588417	48246909	48247016
ENSE00003589542	48288043	48288174
ENSE00003614690	48285106	48285249
ENSE00003649273	48207534	48208139
ENSE00003657142	48255811	48255910
ENSE00003661410	48302750	48304078
ENSE00003661627	48220634	48220765
ENSE00003669638	48259200	48259311
ENSE00003676431	48249575	48249676
ENSE00003744480	48226476	48226571

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 99.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4980 / max 471.4999, expressed in 10 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146541	0.4589	7
146539	0.1469	70
146542	0.0328	3
146540	0.0063	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.91	gold quality
nephron tubule	UBERON:0001231	97.64	gold quality
metanephros cortex	UBERON:0010533	95.66	gold quality
adult mammalian kidney	UBERON:0000082	95.44	gold quality
kidney epithelium	UBERON:0004819	94.96	gold quality
kidney	UBERON:0002113	94.38	gold quality
adult organism	UBERON:0007023	91.90	gold quality
metanephros	UBERON:0000081	91.79	gold quality
renal glomerulus	UBERON:0000074	91.62	gold quality
metanephric glomerulus	UBERON:0004736	91.28	gold quality
lower lobe of lung	UBERON:0008949	87.21	silver quality
cortex of kidney	UBERON:0001225	85.65	gold quality
vena cava	UBERON:0004087	85.28	silver quality
cardia of stomach	UBERON:0001162	84.56	silver quality
sperm	CL:0000019	84.51	silver quality
superficial temporal artery	UBERON:0001614	82.14	silver quality
male germ cell	CL:0000015	81.60	silver quality
saphenous vein	UBERON:0007318	80.80	silver quality
ventral tegmental area	UBERON:0002691	80.51	silver quality
pharyngeal mucosa	UBERON:0000355	80.24	silver quality
subthalamic nucleus	UBERON:0001906	80.00	silver quality
nipple	UBERON:0002030	79.73	silver quality
lateral globus pallidus	UBERON:0002476	79.35	silver quality
pericardium	UBERON:0002407	79.22	silver quality
pons	UBERON:0000988	79.03	silver quality
superior vestibular nucleus	UBERON:0007227	78.88	silver quality
substantia nigra pars reticulata	UBERON:0001966	78.46	silver quality
trigeminal ganglion	UBERON:0001675	78.19	silver quality
substantia nigra pars compacta	UBERON:0001965	77.76	silver quality
dorsal root ganglion	UBERON:0000044	77.42	silver quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	8675.19
E-CURD-119	yes	8535.30
E-CURD-135	yes	5628.25
E-HCAD-10	yes	1179.22
E-GEOD-114530	yes	748.97
E-ANND-3	yes	6.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting SLC12A1, 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-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Presence of a functional NKCC cotransporter in human airway smooth muscle. Basis for defining role of this ion cotransporter in airway smooth muscle function. (PMID:12471046)
• Mutations in hNKCC2 identified in type I Bartter syndrome, when expressed in Xenopus oocytes, result in low expression of normally routed but functionally impaired transporters. Mutations in hNKCC2 are underlying cause of clinical abnormalities. (PMID:12761241)
• Inhibitors for the Na+,K+-ATPase and the Na+-K+-2Cl- cotransporter indicated that rapid increases in in potassium levels upon incubation of resting RBCs (PMID:14528028)
• Review. Based on racial differences in urinary potassium excretion & responses to diuretics, we suggest that a major cause of sodium sensitivity in blacks is an augmented activity of the Na-K-2Cl cotransport in the thick ascending limb of Henle’s loop. (PMID:14967834)
• Late-onset manifestation of Bartter syndrome resulted from residual function of the mutated renal SLC12A1. (PMID:16807401)
• odd-skipped related 1 and sterile20-related, proline-, alanine-rich kinase are likely links between WNK lysine deficient protein kinase 1 and NKCC in a pathway that contributes to volume regulation and blood pressure homeostasis in mammals (PMID:16832045)
• Four novel SLC12A1 mutations were found in two Bartter syndrome type 1 patients. (PMID:17998760)
• 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)
• phenotypic variability in this disease, and the presence of nephropathy suggested that focal segmental glomerulosclerosis might be one of the lesions causing end-stage renal failure in Bartter type I syndrome (PMID:18830715)
• Nephrocalcinosis was constant in KCNJ1 and SLC12A1 mutations. (PMID:19096086)
• Intronic mutation in the SLC12A1 gene is associated with antenatal salt-losing tubulopathy. (PMID:19513753)
• he human NKCC2 is an example of how differential splicing forms the basis for a diversification of transporter protein function (PMID:20146722)
• Screened glioblastomas and oligodendrogliomas for fusion genes by identifying aberrant 5’-3’ expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. (PMID:20196086)
• SLC12A1 mutations are associated with Bartter syndrome. (PMID:20219833)
• In schizophrenia, increased expression levels of OXSR1 and WNK3 may shift the balance of chloride transport by NKCC1 and KCC2 and alter the nature of gamma-aminobutyric acid neurotransmission in the prefrontal cortex. (PMID:20819979)
• Investigated functional consequences of nine rare independed mutations in NKCC2 gene. defects in NKCC2 processing, transport turnover rate, regulation, and ion affinity contribute to impaired transport function in six of the nine identified mutants. (PMID:21209010)
• Data demonstrate that hypotonic low-chloride conditions that activate the WNK1-SPAK and OSR1 pathway promote phosphorylation of NKCC2 isoforms. (PMID:21321328)
• The Wnk3 protein isoforms have a similar effect on SLC12 cotransporters. NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. (PMID:21613606)
• two mutations in the SLC12A1 among patients suffering from bartter and Gitelman syndromes (PMID:21631963)
• NKCC2 is expressed widely in the colonic epithelium in thecolon, especially in the apical membrane. It involves the process of colonic Cl(-) absorption coupled with HCO(3)(-) secretion. (PMID:21867980)
• NKCC2 mutations result in impaired apical targeting and function of NKCC2 transporter and give rise to a pathological phenotype known as type I Bartter syndrome. (Review) (PMID:22211456)
• NKCC1 and NKCC2 were expressed in the gastric mucosa of rat, mouse and human. (PMID:22388656)
• Data show that intracellular association between WNK1 and oxidative stress-responsive 1 (OSR1) is required for stimulation of OSR1 and Na(+), K(+), Cl(-)-Cotransporter NKCC1 and NKCC2 activities by osmotic stress. (PMID:22989884)
• Review summarizes three human disorders that have been linked to the mutation/dysfunction of Na-Cl, Na-K-2Cl, and K-Cl cotransporters (Bartter’s, Gitleman’s, and Andermann’s syndromes). (PMID:23325410)
• overexpression of mammalian plasma-membrane Na+-K+-2Cl- co-transporter NKCC2 in yeast cells complements the phenotypes resulting from the deletion of the VHC1 gene. (PMID:24251329)
• Urinary NKCC2 increased in chronic kidney disease patients and decreased in controls in response to hypertonic saline. (PMID:24970686)
• The association between polymorphisms in KCNJ1, SLC12A1, and 7 other genes and calcium intake and colorectal neoplasia risk was studied. (PMID:25165391)
• Low SLC12A1 urine levels were associated with Bartter syndrome. (PMID:25422309)
• Mutations in SLC12A1 gene is associated with Bartter syndrome. (PMID:25741940)
• A novel variant in the SLC12A1 gene, c.1614T>A, which predicts a change from a tyrosine codon to a stop codon (p.Tyr538Ter) was found in two families with Bartter syndrome type I. (PMID:27748541)
• an association between primary hyperparathyroidism and loss of function mutation of SLC12A1, which may result in an aberrant threshold of the calcium sensing receptor at the level of the kidney, is reported. (PMID:28095294)
• We replicated the methods in a previous study to detect rare and potentially loss-of-function variants in SLC12A3, SLC12A1, and KCNJ1 reducing blood pressure in variant carriers as compared with noncarriers using whole exome sequencing data. Our study confirmed that SLC12A3, SLC12A1, and KCNJ1 are indeed genes protective of hypertension in the general population. (PMID:30113482)
• our results suggest that aberrant exon skipping is one previously unrecognized mechanism by which an exonic variant in SLC12A1 can lead to Bartter syndrome type 1. (PMID:30790175)
• novel missense mutation within the SLC12A1 gene, causing a severe form of antenatal Bartter syndrome type I in Israeli Bedouins (PMID:30977917)
• Differential Effects of STCH and Stress-Inducible Hsp70 on the Stability and Maturation of NKCC2. (PMID:33672238)
• New insights into the role of endoplasmic reticulum-associated degradation in Bartter Syndrome Type 1. (PMID:33973684)
• Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2. (PMID:35011665)
• [Functional characterization of SLC12A1 gene variants in 3 patients with Bartter syndrome type ]. (PMID:35090230)
• Novel SLC12A1 mutations cause Bartter syndrome in two patients with different prognoses. (PMID:35358470)
• Diacidic Motifs in the Carboxyl Terminus Are Required for ER Exit and Translocation to the Plasma Membrane of NKCC2. (PMID:36361553)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc12a1	ENSDARG00000098096
mus_musculus	Slc12a1	ENSMUSG00000027202
rattus_norvegicus	Slc12a1	ENSRNOG00000005367
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), SLC12A3 (ENSG00000070915), SLC12A7 (ENSG00000113504), SLC12A4 (ENSG00000124067), SLC12A5 (ENSG00000124140), SLC12A6 (ENSG00000140199), SLC12A9 (ENSG00000146828), SLC12A8 (ENSG00000221955)

Protein

Protein identifiers

Solute carrier family 12 member 1 — Q13621 (reviewed: Q13621)

Alternative names: Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 1, Kidney-specific Na-K-Cl symporter, Na-K-2Cl cotransporter 2

All UniProt accessions (7): Q13621, A0A2R8Y6V7, A0A8I5KSK6, H0YLJ2, H0YMG9, H0YNW0, Q8IUN5

UniProt curated annotations — full annotation on UniProt →

Function. Renal sodium, potassium and chloride non-electrogenic ion symporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation. It can substitute NH4(+) for K(+), enabling NH4(+) apical transmembrane transport in the medullary thick ascending limb (MTAL). This function is crucial for maintaining ammonium homeostasis by the kidney, particularly during metabolic acidosis.

Subunit / interactions. When phosphorylated, interacts with PPP3CB.

Subcellular location. Apical cell membrane.

Tissue specificity. Kidney; localizes to the thick ascending limbs (at protein level).

Post-translational modifications. Phosphorylated at Ser-91, Thr-100 and Thr-105 by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), promoting its activity.

Disease relevance. Bartter syndrome 1, antenatal (BARTS1) [MIM:601678] A form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS1 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated following phosphorylation by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4).

Domain organisation. The RFXV motif mediates binding with OXSR1/OSR1 and STK39/SPAK.

Similarity. Belongs to the SLC12A transporter family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13621-1	A	yes
Q13621-2	B
Q13621-3	F

RefSeq proteins (3): NP_000329, NP_001171761, NP_001371065 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002443	SLC12A1/SLC12A2	Family
IPR002445	Slc12a1	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), 2 shown:

• K(+)(out) + 2 chloride(out) + Na(+)(out) = K(+)(in) + 2 chloride(in) + Na(+)(in) (RHEA:72395)
• 2 chloride(out) + Na(+)(out) + NH4(+)(out) = 2 chloride(in) + Na(+)(in) + NH4(+)(in) (RHEA:85511)

UniProt features (48 total): topological domain 10, transmembrane region 10, modified residue 9, sequence conflict 6, mutagenesis site 4, sequence variant 3, glycosylation site 2, chain 1, region of interest 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13621-F1	78.39	0.41

Functional residue map

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

Post-translational modifications (9): 61, 91, 95, 100, 105, 118, 120, 130, 148

Glycosylation sites (2): 446, 456

Mutagenesis-validated functional residues (4):

Position	Phenotype
20	abolished interaction with oxsr1/osr1 and stk39/spak and subsequent phosphorylation and activation.
95–100	abolished phosphorylation by oxsr1/osr1 and stk39/spak in vitro.
176	does not affect interaction with oxsr1/osr1 and stk39/spak.
965	does not affect interaction with oxsr1/osr1 and stk39/spak.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-426117	Cation-coupled Chloride cotransporters
R-HSA-5619104	Defective SLC12A1 causes Bartter syndrome 1 (BS1)
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: 231 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_POTASSIUM_ION_TRANSPORT, MODULE_162, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_INORGANIC_ANION_TRANSPORT, CEBPB_01, GOBP_MONOATOMIC_CATION_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, MODULE_368, GOBP_CHLORIDE_TRANSPORT, GOBP_MONOATOMIC_ANION_HOMEOSTASIS, GOBP_TRANSEPITHELIAL_TRANSPORT, GOBP_REGULATION_OF_CELL_SIZE

GO Biological Process (15): monoatomic ion transport (GO:0006811), cell volume homeostasis (GO:0006884), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), chloride ion homeostasis (GO:0055064), potassium ion homeostasis (GO:0055075), sodium ion homeostasis (GO:0055078), transepithelial ammonium transport (GO:0070634), ammonium homeostasis (GO:0097272), chloride transmembrane transport (GO:1902476), potassium ion import across plasma membrane (GO:1990573), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), transmembrane transport (GO:0055085), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (6): sodium:potassium:chloride symporter activity (GO:0008511), sodium:ammonium:chloride symporter activity (GO:7770002), symporter activity (GO:0015293), chloride:monoatomic cation symporter activity (GO:0015377), sodium:chloride symporter activity (GO:0015378), transmembrane transporter activity (GO:0022857)

GO Cellular Component (4): 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	4
transport	2
transmembrane transport	2
monoatomic cation transmembrane transport	2
monoatomic cation homeostasis	2
metal ion transport	2
sodium:chloride symporter activity	2
regulation of cell size	1
cellular homeostasis	1
monoatomic ion transport	1
sodium ion transport	1
monoatomic anion homeostasis	1
transepithelial transport	1
nitrogen compound transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
cellular process	1
potassium ion transport	1
potassium:sodium symporter activity	1
potassium:chloride symporter activity	1
secondary active transmembrane transporter activity	1
chloride transmembrane transporter activity	1
monoatomic anion:monoatomic cation symporter activity	1
monoatomic anion:sodium symporter activity	1
chloride:monoatomic cation symporter activity	1
transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

1418 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC12A1	KCNJ1	P48048	984
SLC12A1	BSND	Q8WZ55	950
SLC12A1	CLCNKB	P51801	946
SLC12A1	STK39	Q9UEW8	930
SLC12A1	WNK4	Q96J92	903
SLC12A1	CLCNKA	P51800	898
SLC12A1	AQP2	P41181	886
SLC12A1	WNK1	P54963	876
SLC12A1	WNK3	Q9BYP7	874
SLC12A1	SLC4A2	P04920	839
SLC12A1	SLC9A3	P48764	836
SLC12A1	OXSR1	O95747	812
SLC12A1	SLC10A3	P09131	776
SLC12A1	REN	P00797	761
SLC12A1	CASR	P41180	753

IntAct

7 interactions, top by confidence:

A	B	Type	Score
OXSR1	SLC12A1	psi-mi:“MI:0407”(direct interaction)	0.440
Stk39	SLC12A1	psi-mi:“MI:0915”(physical association)	0.370
SLC12A1	Oxsr1	psi-mi:“MI:0915”(physical association)	0.370
SLC12A1	ELOVL7	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-29	psi-mi:“MI:0914”(association)	0.350
SLC12A1	pta	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): ATP1A1 (Co-fractionation), SLC12A1 (Positive Genetic), SLC12A1 (Two-hybrid), SLC12A1 (Protein-peptide), HNRNPA2B1 (Cross-Linking-MS (XL-MS)), SLC12A1 (Co-fractionation), SLC12A1 (Co-fractionation), BAG5 (Affinity Capture-MS), CCT8 (Affinity Capture-MS), DNAJC10 (Affinity Capture-MS), DNAJC7 (Affinity Capture-MS), ELOVL7 (Affinity Capture-MS), FN3KRP (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA4 (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

15 interactions.

A	Effect	B	Mechanism
STK39	“up-regulates activity”	SLC12A1	phosphorylation
OXSR1	“up-regulates activity”	SLC12A1	phosphorylation
AMPK	“up-regulates activity”	SLC12A1	phosphorylation
WNK3	“up-regulates activity”	SLC12A1	phosphorylation
SLC12A1	“up-regulates quantity”	chloride	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1062 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	55
Uncertain significance	366
Likely benign	429
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067800	NM_000338.3(SLC12A1):c.3164+1G>A	Pathogenic
1070102	NM_000338.3(SLC12A1):c.1405A>T (p.Arg469Ter)	Pathogenic
1320258	NM_000338.3(SLC12A1):c.382C>T (p.Arg128Ter)	Pathogenic
1342020	NM_000338.3(SLC12A1):c.223C>T (p.Gln75Ter)	Pathogenic
1458179	NC_000015.9:g.(?48547988)(48548127_?)del	Pathogenic
1997109	NM_000338.3(SLC12A1):c.2233A>T (p.Lys745Ter)	Pathogenic
2202999	NM_000338.3(SLC12A1):c.1166dup (p.Ala390fs)	Pathogenic
2428826	NM_000338.3(SLC12A1):c.2281C>T (p.Arg761Ter)	Pathogenic
2500697	NM_000338.3(SLC12A1):c.1966C>T (p.Gln656Ter)	Pathogenic
265999	NM_000338.3(SLC12A1):c.1163del (p.Phe388fs)	Pathogenic
2692633	NM_000338.3(SLC12A1):c.1614T>G (p.Tyr538Ter)	Pathogenic
2706867	NM_000338.3(SLC12A1):c.2244T>G (p.Tyr748Ter)	Pathogenic
2711618	NM_000338.3(SLC12A1):c.2654C>A (p.Ser885Ter)	Pathogenic
2726687	NM_000338.3(SLC12A1):c.2150_2151del (p.Phe717fs)	Pathogenic
2735542	NM_000338.3(SLC12A1):c.699del (p.Ile233fs)	Pathogenic
2736214	NM_000338.3(SLC12A1):c.904del (p.Arg302fs)	Pathogenic
2736215	NM_000338.3(SLC12A1):c.1411C>T (p.Arg471Ter)	Pathogenic
2736216	NM_000338.3(SLC12A1):c.1614T>A (p.Tyr538Ter)	Pathogenic
2736217	NM_000338.3(SLC12A1):c.2952_2955del (p.Asn984fs)	Pathogenic
2746246	NM_000338.3(SLC12A1):c.3098del (p.Ser1033fs)	Pathogenic
2760861	NM_000338.3(SLC12A1):c.1419del (p.Glu473fs)	Pathogenic
2765181	NM_000338.3(SLC12A1):c.524_525del (p.Val175fs)	Pathogenic
2800345	NM_000338.3(SLC12A1):c.186dup (p.Arg63Ter)	Pathogenic
2803768	NM_000338.3(SLC12A1):c.2964G>A (p.Trp988Ter)	Pathogenic
2804635	NM_000338.3(SLC12A1):c.3075del (p.Glu1025fs)	Pathogenic
2808015	NM_000338.3(SLC12A1):c.2628del (p.Asp877fs)	Pathogenic
2824459	NM_000338.3(SLC12A1):c.2963G>A (p.Trp988Ter)	Pathogenic
2828087	NM_000338.3(SLC12A1):c.2744G>A (p.Trp915Ter)	Pathogenic
2835557	NM_000338.3(SLC12A1):c.2507del (p.Gln836fs)	Pathogenic
2840113	NM_000338.3(SLC12A1):c.64C>T (p.Gln22Ter)	Pathogenic

SpliceAI

4691 predictions. Top by Δscore:

Variant	Effect	Δscore
15:48207526:A:AG	acceptor_gain	1.0000
15:48220623:A:AG	acceptor_gain	1.0000
15:48220624:T:G	acceptor_gain	1.0000
15:48220625:A:AG	acceptor_gain	1.0000
15:48220625:AAAAT:A	acceptor_gain	1.0000
15:48220626:A:G	acceptor_gain	1.0000
15:48220633:GA:G	acceptor_gain	1.0000
15:48220715:G:GT	donor_gain	1.0000
15:48220752:TGAA:T	donor_gain	1.0000
15:48220754:AAAG:A	donor_gain	1.0000
15:48220997:G:GG	donor_gain	1.0000
15:48230392:GGA:G	acceptor_gain	1.0000
15:48230392:GGAGA:G	acceptor_gain	1.0000
15:48230499:CAAAG:C	donor_loss	1.0000
15:48230500:AAAG:A	donor_loss	1.0000
15:48230502:AGGTA:A	donor_loss	1.0000
15:48230503:GGTAA:G	donor_loss	1.0000
15:48230504:G:GA	donor_loss	1.0000
15:48230505:T:A	donor_loss	1.0000
15:48244747:CCACA:C	acceptor_loss	1.0000
15:48244748:CACA:C	acceptor_loss	1.0000
15:48244750:CAGGG:C	acceptor_loss	1.0000
15:48244751:A:AG	acceptor_gain	1.0000
15:48244751:A:T	acceptor_loss	1.0000
15:48244751:AG:A	acceptor_gain	1.0000
15:48244751:AGG:A	acceptor_gain	1.0000
15:48244752:G:GG	acceptor_gain	1.0000
15:48244752:GG:G	acceptor_gain	1.0000
15:48244752:GGG:G	acceptor_gain	1.0000
15:48244880:G:GG	donor_gain	1.0000

AlphaMissense

7261 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:48220748:T:A	W179R	1.000
15:48220748:T:C	W179R	1.000
15:48220757:G:C	G182R	1.000
15:48220928:G:A	C187Y	1.000
15:48220929:C:G	C187W	1.000
15:48220934:T:C	L189P	1.000
15:48220938:C:A	N190K	1.000
15:48220938:C:G	N190K	1.000
15:48220942:T:A	W192R	1.000
15:48220942:T:C	W192R	1.000
15:48220945:G:A	G193R	1.000
15:48220945:G:C	G193R	1.000
15:48220946:G:A	G193E	1.000
15:48220955:T:A	L196H	1.000
15:48220957:T:C	F197L	1.000
15:48220959:C:A	F197L	1.000
15:48220959:C:G	F197L	1.000
15:48226526:G:A	G227R	1.000
15:48226526:G:C	G227R	1.000
15:48226527:G:A	G227E	1.000
15:48226545:T:A	I233K	1.000
15:48226547:G:C	A234P	1.000
15:48226555:C:A	N236K	1.000
15:48226555:C:G	N236K	1.000
15:48226556:G:A	G237R	1.000
15:48226556:G:C	G237R	1.000
15:48226556:G:T	G237W	1.000
15:48226557:G:A	G237E	1.000
15:48229192:G:A	G243E	1.000
15:48229204:T:C	L247P	1.000

dbSNP variants (sampled 300 via entrez): RS1000015081 (15:48223040 A>G), RS1000037651 (15:48265400 A>G), RS1000047382 (15:48257778 T>C), RS1000052000 (15:48302511 T>A,G), RS1000080897 (15:48214467 A>C), RS1000082080 (15:48222677 C>A,T), RS1000171319 (15:48253571 T>C), RS1000212066 (15:48283197 C>T), RS1000225896 (15:48240630 G>A), RS1000227475 (15:48284100 A>C), RS1000247657 (15:48276522 A>C,G), RS1000267470 (15:48291512 T>C), RS1000289090 (15:48234470 C>T), RS1000340536 (15:48276730 T>C), RS1000357512 (15:48278303 C>T)

Disease associations

OMIM: gene MIM:600839 | disease phenotypes: MIM:601678, MIM:607364, MIM:174900, MIM:263800

GenCC curated gene-disease

Disease	Classification	Inheritance
antenatal Bartter syndrome	Definitive	Autosomal recessive
Bartter disease type 1	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete antenatal Bartter syndrome	Definitive	AR

Mondo (8): Bartter disease type 1 (MONDO:0100344), Bartter syndrome (MONDO:0015231), Bartter disease type 3 (MONDO:0011822), nephrocalcinosis (MONDO:0001567), nephrolithiasis (MONDO:0008171), juvenile polyposis syndrome (MONDO:0017380), Gitelman syndrome (MONDO:0009904), (MONDO:0100343)

Orphanet (5): Bartter syndrome (Orphanet:112), Bartter syndrome type 1 (Orphanet:620217), Bartter syndrome type 3 (Orphanet:93605), Juvenile polyposis syndrome (Orphanet:2929), Gitelman syndrome (Orphanet:358)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000103	Polyuria
HP:0000111	Renal juxtaglomerular cell hypertrophy/hyperplasia
HP:0000121	Nephrocalcinosis
HP:0000127	Renal salt wasting
HP:0000128	Renal potassium wasting
HP:0000841	Hyperactive renin-angiotensin system
HP:0000843	Hyperparathyroidism
HP:0000848	Increased circulating renin concentration
HP:0000859	Increased circulating aldosterone concentration
HP:0000934	Chondrocalcinosis
HP:0000938	Osteopenia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001281	Tetany
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001561	Polyhydramnios
HP:0001563	Fetal polyuria
HP:0001622	Premature birth
HP:0001944	Dehydration
HP:0001945	Fever
HP:0001960	Hypokalemic metabolic alkalosis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002150	Hypercalciuria
HP:0002632	Low-to-normal blood pressure
HP:0002900	Hypokalemia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002118_19	Metabolite levels (Pyroglutamine)	8.000000e-06
GCST003252_22	Systemic lupus erythematosus	1.000000e-07
GCST90002388_147	Lymphocyte count	9.000000e-11
GCST90002389_298	Lymphocyte percentage of white cells	8.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005408	pyroglutamine measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
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
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
C537652	Bartter syndrome, antenatal type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1874 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

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

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
bumetanide	Inhibition	6.48	pIC50
piretanide	Inhibition	5.97	pIC50
furosemide	Inhibition	5.15	pIC50

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
tris(1,3-dichloro-2-propyl)phosphate	decreases activity	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Zoledronic Acid	decreases expression	1
Fulvestrant	decreases methylation	1
Benzo(a)pyrene	affects methylation	1
Chloroquine	decreases expression	1
Estradiol	decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Zinc Oxide	decreases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4YA	WMUi019-A	Induced pluripotent stem cell	Female

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