KCNT2 encodes a sodium-activated and chloride-activated potassium channel that produces rapidly activating outward rectifier potassium currents and contributes to the regulation of neuronal excitability. The channel is expressed across multiple tissue types, including pancreatic delta cells, and functions in potassium ion transport across the plasma membrane. Pathogenic variants in KCNT2 cause developmental and epileptic encephalopathy 57 (DEE57), a severe early-infantile disorder characterized by developmental delay or intellectual disability (present in 21 of 22 individuals with available information), seizures in approximately 60% of affected patients, altered muscle tone, and dysmorphisms 1. KCNT2 variants can exhibit either gain-of-function or loss-of-function mechanisms; among tested variants, eight showed gain-of-function features and six demonstrated loss-of-function properties when expressed in vitro 1. Loss-of-function variants impair neuronal excitability—neurons lacking functional Kcnt2 display increased excitability and enhanced seizure susceptibility compared to wild-type controls 2. Additionally, a genome-wide association study in diabetic polyneuropathy identified a significant association at the KCNT2 locus with neuropathic pain intensity 3. Clinically, pharmacological responses differ by variant type: quinidine and fluoxetine block gain-of-function variants, while loxapine and riluzole show variable effects on loss-of-function variants 1. This unique pharmacological profile for each variant suggests the need for functional characterization to enable targeted, variant-specific therapeutic approaches.