Congratulations to the Garcia-Marcos lab for their recent publication investigating the molecular basis for disease-linked mutations in G proteins. Heterotrimeric G proteins are molecular switches that control signal transduction. Many mutations in G proteins have been shown to cause human diseases. But not all these mutations are made equal. They found that two identical mutations can cause different diseases even if present in highly similar G proteins. By dissecting the biochemical properties of the different mutants, they elucidated the basis of how an identical mutation can make one G protein hyperactive in cancer and the second G protein inactive in rare inherited disease.