An integrated toolset for the analysis of de novo (sporadic) genetic sequence variants. denovolyzeR implements a mutational model that estimates the probability of a de novo genetic variant arising in each human gene, from which one can infer the expected number of de novo variants in a given population size. Observed variant frequencies can then be compared against expectation in a Poisson framework. denovolyzeR provides a suite of functions to implement these analyses for the interpretation of de novo variation in human disease.