The reasons why six rare variants in this cohort (Fig. 4) are classified as VUS were as follows: In some patients, TNSALP activity was only in the lower reference range (c.-81G > A), PLP changes were inconsistent within a family for the same variant (c.565_575delinsAG), there were few or no typical symptoms or signs of HPP (c.286G > C, c.436G > A, c.625A > T) or skeletal involvement was absent (c.818C > T). The gene discussed is ALPL; the disease is hypophosphatasia.