By characterizing the biophysical properties of 6 variants by 2‐electrode voltage‐clamp method (TEVC), Western blot analysis, membrane trafficking analysis, and 3D modeling, we demonstrate that HCN2 variants are associated with a more severe and broader clinical spectrum of neurodevelopmental disorders than previously reported, and confirm its involvement in DEE. The gene discussed is HCN2; the disease is neurodevelopmental disorder.