Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of speciﬁc activating missense mutations. Although epidemiological studies connect speciﬁc alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-speciﬁc genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-speciﬁc frequencies of mutant alleles. Consistent with experimental studies that have identiﬁed distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissuespeciﬁc comutation network. Moreover, we identify tissue-speciﬁc genetic dependencies associated with speciﬁc mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-speciﬁc, underscoring the complexity that drives their clinical consequences.