We found FAM190A transcripts to have internal rearrangements in 40% (19/48) of unselected human cancers. Most of these tumors (84%) had in-frame structures, 94% of which involved deletion of exon 9. The FAM190A gene is located at 4q22.1 in a region of common fragility, FRA4F. Although normally stable in somatic cells, common fragile sites can be hotspots of rearrangement in cancer. The genomic deletion patterns observed at some sites, including FRA4F at 4q22.1, are proposed to be the result of selection for disrupted tumor-suppressor genes. Our evidence, however, indicated additional patterns for FAM190A. We found genomic deletions accounted for some FAM190A in-frame structures, and cases pre-selected for FAM190A genomic deletions had a yet higher prevalence of FAM190A rearrangements. Our evidence of widespread in-frame heterozygous and homozygous rearrangements affecting this gene in tumors of multiple types leads speculation on structural grounds that the mutant forms may retain, provide new, or possibly convey dominant-negative functions. Although a functionally uncharacterized gene, it is evolutionary conserved across vertebrates. In addition to its potential oncogenic role, the in-frame deletions predict the formation of cancer-specific FAM190A peptide sequences (neo-antigens) with potential diagnostic and therapeutic usefulness.