We recently reported the molecular cloning of a novel transforming rat brain cDNA, rbc7, that encodes a Ras activator (Ebinu et al. Science 280, p. 1082, 1998). We proposed that this cDNA is a 5' and 3' truncated version of a larger normal transcript that encodes a predicted 90-kDa protein which we called RasGRP (Ras guanyl nucleotide releasing protein). We have now studied the structure of the mouse and human sequences and confirmed our conclusions about the nature of the 5' truncation. The human gene has been localized to 15q15 by an in situ hybridization technique, while the mouse gene has been positioned on Chr 2 near thrombospondin by linkage analysis. The relatedness of RasGRP to another human sequence and a hypothetical nematode protein are also discussed.