<p>KCNQ2 is a member of the voltage-gated potassium (Kv) channel family and regulates neuronal activity through potassium ion efflux. Pathogenic variants of KCNQ2 induce aberrant neuronal activity and cause two types of epilepsy: self-limited familial neonatal epilepsy (SLFNE) and developmental and epileptic encephalopathies (DEE). However, the molecular mechanism by which these pathogenic variants influence KCNQ2 expression remains unclear. Here, we show N-terminal and C-terminal fragments derived from mouse KCNQ2 (KCNQ2^S−N and KCNQ2^S−C, respectively), whose amounts differed significantly across variants compared with wild type, whereas those of full-length KCNQ2 (KCNQ2^F) remained unchanged. Of particular interest, two variants at the same codon, Y284C and Y284D, which are associated with distinct clinical phenotypes—self-limited familial neonatal epilepsy (SLFNE) and developmental and epileptic encephalopathy (DEE), respectively—exerted opposite effects on the fragment: Y284C increased the amounts of both KCNQ2 fragments, whereas Y284D decreased it compared with the wild type. As both KCNQ2^S−N and KCNQ2^S−C were localized in the plasma membrane, both fragments were suggested to be post-translational products resulting from a cleavage of full-length KCNQ2. This novel post-translational cleavage was observed in neuronal cells and appears to be evolutionarily conserved. Although the role of this post-translational modification in epilepsy remains unknown, it may be elucidated through future studies.</p>