Chloride channel protein ClC-Ka is a protein that in humans is encoded by the CLCNKA gene. Multiple transcript variants encoding different isoforms have been found for this gene. Function This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Gene variants CLCNKA encodes one of the two major chloride channels found in the kidney, the ClC-Ka channel (the other class being the ClC-Kb from CLCNKB). The CLCNKA gene is subject, like all genes, to variation due to single-nucleotide polymorphisms (SNPs), in which a single base (A, T, C, or G) is randomly replaced by another base. SNPs in the coding regions of CLCKNA may have consequent changes in the amino acid sequence of the ClC-Ka chloride channel leading to altered functional capacities and subsequent physiological alterations. Four SNPs (rs848307, rs1739843, rs1010069, and rs1805152) have been associated with increased salt-sensitivity by displaying an irregularly large increase in blood pressure following modest salt (Na+) intake, despite regular heart rate, blood pressure, and plasma renin levels before the salt ingestion. Of particular interest is a common SNP leading to the amino acid Arginine at the 83rd position to be replaced by Glycine. This variant is found to exist in approximately half of all caucasians, while a quarter of caucasians are homozygous for the allele. Although mainly studied in the context of caucasians, the SNP actually exists with a greater frequency in people of African descent, where the gene frequency is 70%. This SNP (rs10927887) was originally implicated in congestive heart failure after investigations into the heat shock protein HSPB7 showed that the CLCNKA gene was in linkage disequilibrium, meaning that the two genes are often not separated during recombination. The CLCNKA variant was then shown to be the cause of the pathology. Pathology The four SNPs found to be associated with salt sensitivity consequently predispose such cardiovascular problems as left ventricular hypertrophy and dysfunction of the endothelium. The Arg83Gly SNP specifically results in a large reduction in the flow of chloride ions through the ClC-Ka channel in the thin and thick ascending limb of