A clinical proteogenomic analysis of 100 pancreatic ductal adenocarcinoma samples was able to precisely identify mutations in TP53, KRAS, SMAD4, CDKN2A, ARID1A, and ROBO2, including mutations in the KDM6A and PREX2 driver genes, which drive PDAC tumorigenesis. The gene discussed is SMAD4; the disease is pancreatic ductal adenocarcinoma.