Compared to M class ICCs (92–147 somatic mutations; n = 5) with a relative deficit of CNAs, C class ICCs (54–84 mutations; n = 5) harbor recurrent focal CNAs including deletions involving CDKN2A, ROBO1, ROBO2, RUNX3, and SMAD4. We also show that transcriptome sequencing can be used for expression-based ICC categorization but the somatic mutation calling from the transcriptome can be heavily influenced by the gene expression level and potentially, by posttranscriptional modification such as nonsense mediated decay. Here, SMAD4 is linked to intrahepatic cholangiocarcinoma.