In this study, all patients with hotspot variants (p.Arg357, p.Leu489, p.Ala492, p.Ile494, and p.Gly496) associated with epilepsy with moderate to severe ID/DD clustered in S4 and S6, while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered, suggesting a molecular sub‐regional effect of KCNH1 variants. Here, KCNH1 is linked to epilepsy.