Mice lacking K+-Cl− cotransporter 2 (KCC2; also known as SLC12A5) have seizures. Investigating possible KCC2 mutations in human families with seizure disorders, the authors identified a variant, KCC2-R952H, that was associated with febrile seizures. Mouse cortical neurons transfected with KCC2-R952H showed deficient Cl− extrusion and reduced surface expression of the transporter. In vitro experiments showed that the variant impairs the role of KCC2 in dendritic spine formation. These findings provide a potential molecular basis for KCC2-R952H-induced susceptibility to seizures.