DOME is a somatic driver mutation prediction algorithm and GUI-based resource that allows for the analysis of singleton mutations that drive tumor development and progression. It has the potential to identify driver mutations and enhance our understanding of cancer biology for personalized cancer therapy. DOME works in tandem with recurrence-based statistical approaches to identify potential driver mutations among poorly recurring singleton mutations. Its analysis incorporates domain conservation, mutation distribution, somatic amino-acid change propensity, and functional and biochemical residue context within protein structures. DOME is suitable for exploring missense mutations in protein positions across human proteome domains and for downstream analysis of sequencing-derived somatic mutations.