Most of the mutations responsible for genetic disease are remarkably subtle, considering the dramatic effects they may have on the phenotype. A change in just one of many thousand bases in a gene can be sufficient to disrupt and thus alter or eliminate the expression of a protein product. On the other hand, genetic variation is common from person to person and is usually of no phenotypic consequence. Benign changes may occur in regions that do not encode protein or do alter the properties of the protein encoded by a gene. The challenge in the molecular diagnosis of gene mutations. © 1995, Massachusetts Medical Society. All rights reserved.