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The KCC2 cotransporter establishes the low neuronal Cl⁻ levels required for GABA_A and glycine (Gly) receptor‐mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been documented in human disease. Here, we report two non‐synonymous functional variants in human KCC2, R952H and R1049C, exhibiting clear statistical association with idiopathic generalized epilepsy (IGE). These variants reside in conserved residues in the KCC2 cytoplasmic C‐terminus, exhibit significantly impaired Cl⁻‐extrusion capacities resulting in less hyperpolarized Gly equilibrium potentials (E_Gly), and impair KCC2 stimulatory phosphorylation at serine 940, a key regulatory site. These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be …