With recent interest in the molecular mechanisms responsible for Fabry disease, the number of known mutations in the GLA gene which encodes alpha-galactosidase A has expanded considerably. Combining a large database of Fabry disease-causing mutations with the recently determined crystal structure of human alpha-galactosidase A allows for a new understanding of the atomic defects in the protein responsible for Fabry disease. We have conducted a systematic survey of the known Fabry disease-causing mutations and analyzed the mutations in the context of the alpha-galactosidase A structure. We have applied quantitative methods for identifying the plausible effect of each mutation on the alpha-galactosidase A protein. We present the analysis of 331 different defects in the GLA gene leading to non-native proteins in patients with Fabry disease. These mutations include 278 missense mutations, 49 nonsense mutations, and four single amino acid deletions.Over half of the residues in the protein have been found to have changes in patients with Fabry disease. Most of these genetic mutations lead to disruption of the hydrophobic core of the protein, thus Fabry disease is primarily a disease of protein-folding. Further understanding of alpha-galactosidase A, one of the best studied members of the lysosomal storage disease family, will lead to increased understanding of other lysosomal storage diseases and other protein-folding diseases.