Fabry disease is an inborn error of glycolipid catabolism resulting from lesions in the gene encoding alpha-galactosidase (GLA). To elucidate the basis of Fabry disease, we constructed structural models of mutant GLAs responsible for the disease and calculated indexes, i.e., the numbers of atoms affected in the main chain and side chain of each mutant GLA, the root-mean-square distance values, and the solvent-accessible surface-area values, based on 212 Fabry amino acid substitutions previously reported (196 classic and 16 variant). As two therapeutic options, enzyme replacement and enzyme enhancement, are now available for this disease, proper prediction of the natural outcome and therapeutic efficiency based on the molecular evidence for individual cases are critical for patients' quality of life. Our results revealed that structural changes in the classic Fabry group were generally large and tended to be in the core region of a protein or located in the functionally important region, including the active-site pocket. On the other hand, structural changes in the variant Fabry group were small or localized on the surface of the molecule far away from the active site. We focused on structural changes due to amino acid substitutions for which substrate analogues are effective for improving the stability or transportation of mutant GLAs, and the results of the study revealed that they are small or localized on the molecular surface, regardless of the phenotype. Coloring of affected atoms based on distances between wild type and mutant ones clearly showed the characteristic structural changes in the GLA protein geographically and subquantitatively. Structural investigation is useful for elucidation of the basis of Fabry disease and predicting disease outcome.