As opposed to the decreased Wnt signaling apparently observed for the variants (p.Leu104Pro and p.Pro103Ala) that disrupt the RSPO-binding sites only, the increased Wnt signaling were observed or predicted by our modeling for deleterious variants in the RING domain (p.Cys293Tyr, p.Cys296Tyr, p.Cys319Tyr, p.Arg307Gln, p.Pro322Arg, and p.Arg334Trp) and for the deleterious variant p.Pro179Leu in the protease-associated domain, reflecting a higher prevalence of macrocephaly than that of microcephaly in our cohort. Here, RSPO1 is linked to Macrocephaly.