We identified four mutation signatures in our cohort with a high prevalence of signature C. Our combined computational prediction-based prioritization and functional analysis identified that GXYLT1 is a potentially novel oncogene that promotes the metastasis of CRC via the Notch and MAPK pathways, and the stop-gain mutant GXYLT1S212* promoted a stronger malignant phenotype in CRC by activating MAPK signaling. The gene discussed is GXYLT1; the disease is colorectal carcinoma.