[Causal mutation or rare polymorphism? Frequency of mutation not found in 3 chromosome is less than 3 divided by n].
ABSTRACT The problem of distinguishing rare polymorphism from deleterious mutations is an important question in molecular medicine. In order to estimate the frequency of a sequence variation, unrelated normal individuals are usually screened for the mutation concerned. A sequence variation that is not found in non-affected individuals becomes more likely to be the cause of the disease. The aim of this paper is to provide a practical estimation of the fortuitous occurrence of a private polymorphism in one or several patients. The frequency of a sequence variation is not difficult to estimate in a population. The 95% upper frequency limit of a gene variant not observed in n chromosomes is 1-n+1 square root of 0.05. This can conveniently be approximated as 3/n. While the likelihood for finding a sequence variation only in patients is easily calculated, it is practically impossible to compute the exact probability that this variation is indeed the cause of the disease.