In summary, our findings on the likely loss-of-function pathogenic variants [67] of the Cav1.3 encoding CACNA1D gene in ALS could be indicative of the irreversible Piezo2 microdamage-derived dysregulated or lost pain pathways in the spinal dorsal horn of ALS, although further functional analyses are needed to prove the link between the detected variants and the altered cellular functions as well. Here, PIEZO2 is linked to amyotrophic lateral sclerosis.