The simultaneous analysis of closely linked nucleotide substitutions has recently become possible. However, it is not known whether the construction of molecular haplotypes will be a generally useful strategy for nuclear genes. Furthermore, whereas mobility-shift methods are widely used for the discovery of nucleotide substitutions, the yield of these methods has rarely been evaluated. This paper investigates these issues in non-coding regions of ALDH2, the gene that encodes aldehyde dehydrogenase 2 (ALDH2). Screening 20 Europeans, 20 native Americans, and 20 Asians by using restriction enzyme and single-strand conformation polymorphism (SSCP) analysis has revealed 16 variable sites. SSCP yields slightly fewer than the number of nucleotide substitutions predicted by the restriction enzyme digests. Estimates of nucleotide diversity are similar to those of other genes, suggesting that the pattern of polymorphism in ALDH2 offers a preview of what can be expected in many human nuclear genes. Eight of the variable sites discovered here and four sites discovered by others have been genotyped in 756 people from 17 populations across five continents. An expectation-maximization method has used to estimate haplotype states and frequencies. Only three haplotypes are common worldwide, and a fourth haplotype is common in, but private to, Asia. Although allele frequencies differ among sites, linkage disequilibrium is almost maximal across ALDH2. This suggests that haplotype construction at ALDH2 is particularly successful. The ALDH2 result, in conjunction with linkage disequilibrium results from other genes, indicates that haplotype construction will be a generally useful genomic strategy.