ALDH2, which has a lower KM for acetaldehydes than ALDH1 and acts predominantly in the mitochondrial matrix, is the main enzyme in acetaldehyde metabolism and has three genotypes. A single point mutation (G → A) at exon 12 of the ALDH2 gene causes a replacement of glutamine with lysine at residue 487, resulting in the ALDH2K enzyme. ALDH2K has an increased KM for NAD+, rendering it virtually inactive at cellular concentrations of NAD+. Since ALDH2 is a randomized tetramer, the hetero-mutated genotype is reduced to only 6% activity compared to wild type, while homo-mutated genotypes have virtually zero enzyme activity. The ALDH2-deficient subunit is dominant in hybridization with a wild type subunit, resulting in inactivation of the isozyme by interfering with catalytic activity and increasing turnover. ALDH2 genetic variation has been closely correlated with alcohol dependence, with heterozygotes at a reduced risk compared to wild type homozygotes and individual homozygotes for the ALDH2-deficient at a very low risk for alcoholism.