Finally, “private” large-size-effect variants may be identified by chance, such as in the very rare families carrying mutations of KCNK18 or CSNK1D. In these families, the strong penetrance of the migraine phenotype could result from the cosegregation of the “private” large-size-effect mutation and a pro-migraine genetic background due to a high PRS, whereas most carriers of the same rare variant would not express a migraine phenotype thanks to a non-permissive genetic background. This evidence concerns the gene KCNK18 and migraine disorder.