GUSB and neoplasm: Here, we mapped somatic mutations generated from 10 tumor‐normal matched HNSCC samples into allosteric sites to prioritize the mutated allosteric proteins via whole‐exome sequencing and AlloDriver, identifying the specific mutation H351Q in β‐glucuronidase (GUSB), a lysosomal enzyme, as a novel allosteric driver mutation, which considerably encouraged HNSCC progression both in vitro and in vivo.