The RNAse A mismatch cleavage method was used to analyze genomic variability in RNA and DNA systems. However, there is no method which relates the digestion patterns observed to the extent of genetic variation. Here we report computer simulations which provide a simple estimator of genetic distances from the comparison of RNAse A digestion patterns. The results show that the number of non-shared fragments is proportional to the number of mutations between each pair of sequences compared. This prediction is supported by the comparison of the RNAse A mismatch patterns and the nucleotide sequences of a set of influenza A (H3N2) hemagglutinin genes. The procedure allows a quantitative and reliable use of the RNAse A mismatch cleavage method.