Sodium/potassium/calcium exchanger 5 (NCKX5), also known as solute carrier family 24 member 5 (SLC24A5), is a protein that in humans is encoded by the SLC24A5 gene that has a major influence on natural skin colour variation. The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger family. Sequence variation in the SLC24A5 gene, particularly a non-synonymous SNP changing the amino acid at position 111 in NCKX5 from alanine to threonine, has been associated with differences in skin pigmentation. The SLC24A5 gene's derived threonine or Ala111Thr allele (rs1426654) has been shown to be a major factor in the light skin tone of Europeans compared to Sub-Saharan Africans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and West Africans. Possibly originating as long as 19,000 years ago, it has been the subject of selection in the ancestors of Europeans as recently as within the last 5,000 years, and is fixed in modern European populations. It was introduced into Khoisan people via "back-to-Africa" migration around 2,000 years ago is partly responsible for their differing skin tone to most other African populations. Gene The SLC24A5 gene, in humans, is located on the long (q) arm of chromosome 15 on position 21.1, from base pair 46,200,461 to base pair 46,221,881. Protein NCKX5 is 43 kDa protein that is partially localized to the trans-Golgi network in melanocytes. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in melanin pigment production. Site-directed mutagenesis corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity. Effect on skin color SLC24A5 appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. Evidence in the International HapMap Project database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary alleles differing by only one nucleotide, changing the 111th amino acid from alanine to threonine, abbreviated "A111T". The derived threonine allele (Ala111Thr; also known as A111T or Thr111) represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in