Accumulation of DNA mutations alters amino acid sequence in the key domains of oncoproteins, leading to cellular malignant transformation. Due to redundancy of the genetic code, the same amino acid alteration can be achieved by multiple distinct genetic mutations, which are considered functionally identical and not actively distinguished in the current cancer genome research. For the first time, we analyzed the distribution of codon level transitions acquired by somatic mutations in human cancers. By analyzing the ~2.5 million nonsynonymous somatic single nucleotide variations (SNVs) found in the COSMIC database, we found 41 recurrent amino acid alterations whose DNA changes are significantly biased toward a specific codon transition. Additional analyses partially identified functional discrepancies between the favored and avoided codon transitions in terms of mutational process, codon usage, alternative splicing, and mRNA stability.