A mutated KRAS protein is frequently observed in human cancers. Traditionally, 
the oncogenic properties of KRAS missense mutants at position 12 (G12X) have 
been considered as equal. Here, by assessing the probabilities of occurrence of 
all KRAS G12X mutations and KRAS dynamics we show that this assumption does not 
hold true. Instead, our findings revealed an outstanding mutational bias. We 
conducted a thorough mutational analysis of KRAS G12X mutations and assessed to 
what extent the observed mutation frequencies follow a random distribution. 
Unique tissue-specific frequencies are displayed with specific mutations, 
especially with G12R, which cannot be explained by random probabilities. To 
clarify the underlying causes for the nonrandom probabilities, we conducted 
extensive atomistic molecular dynamics simulations (170 μs) to study the 
differences of G12X mutations on a molecular level. The simulations revealed an 
allosteric hydrophobic signaling network in KRAS, and that protein dynamics is 
altered among the G12X mutants and as such differs from the wild-type and is 
mutation-specific. The shift in long-timescale conformational dynamics was 
confirmed with Markov state modeling. A G12X mutation was found to modify KRAS 
dynamics in an allosteric way, which is especially manifested in the switch 
regions that are responsible for the effector protein binding. The findings 
provide a basis to understand better the oncogenic properties of KRAS G12X 
mutants and the consequences of the observed nonrandom frequencies of specific 
G12X mutations.