We observed that many tauopathy-associated PERK variants target the ER stress–sensing luminal domain (Fig. 1E), and modeling of amino acid substitutions at residues 136 and 240 on the mammalian crystal structure of the PERK luminal domain revealed disruption of H-bonds between these two residues when converted to disease variants (Fig. 2). Here, EIF2AK3 is linked to tauopathy.