A recent crystallographic study of Sig1R revealed that a pair of hydrogen bonds formed by Glu102, Val36, and Phe37 in Sig1R tethers its cytosolic domain to the transmembrane domain (Schmidt et al, 2016), providing a structural explanation for instability of the ALS‐linked Sig1R variants. Here, SIGMAR1 is linked to amyotrophic lateral sclerosis.