Here we demonstrate two characteristically different classes or types of gene sequence variation in the circumsporozoite protein from Plasmodium falciparum. Some patterns of sequence variation suggest, or are at least consistent with, Mendelian inheritance. We show here that patterns of sequence variation at specific positions, however, introduce homoplasy (similarity or identity not directly attributable to common ancestry) into the relationship between parasites. The demonstration of extensive homoplasy in a malaria gene raises questions about the validity of familial relationships established among parasites with polymorphic markers. We suggest that homoplasy at particular positions could mark a site of biological pressure on the parasite where interaction of the site with factors in the environment affects the success of the parasite population. This may well emphasize the importance of the circumsporozoite protein in malarial vaccine constructs as discussed below. Further we offer an approach to structural analysis that demonstrates and quantitates the degree of homoplasy in particular positions of a protein.