The ALS-associated SPTLC1 variants, located near the transmembrane interface between SPTLC1 and ORMDL3, might slightly modulate the ORMDL conformation in the SPT-ORMDL complex that allosterically alters the ceramide pocket and/or the conformation of the ORMDL N-terminus, resulting in attenuated ceramide binding and/or ceramide-mediated SPT-ORMDL inhibition. This evidence concerns the gene ORMDL3 and amyotrophic lateral sclerosis.