In fact, several studies have identified obesity-associated missense variants in the SIM1 bHLH (Thr46Arg, Glu62Lys) [8,36], and PAS (Ser71Arg, Ile128Thr, Gln152Glu, Arg171His, Leu238Arg) domains, all of which are involved in forming the heterodimer with ARNT2 [9]. The gene discussed is SIM1; the disease is obesity due to melanocortin 4 receptor deficiency.