Here, we took advantage of the increasing knowledge of SORL1 function and structured domains (Fig. 1) and we learned from the effect of specific missense variants on the function of proteins that share domains with SORL1, such as those in the low-density-lipoprotein receptor (LDLR)-family and Fibronectin-like proteins, which are associated with familial diseases like Familial Hypercholesterolemia (FH) and holoprosencephaly (Fig. 2). The gene discussed is SORL1; the disease is holoprosencephaly.