Abnormal UBA1 activity or ubiquitination causes or drives many human diseases, such as cancer, major neurodegenerative diseases, Angelman syndrome, VEXAS syndrome, and spinal muscular atrophy, as well as aging, highlighting the importance of the discovery of small-molecule modulators of UBA1 activity for research and therapeutic purposes. This evidence concerns the gene UBA1 and proximal spinal muscular atrophy.