Inclusion Criteria:  Aim 1-  Diagnosis of Hypophosphatasia based on clinical features that include  History consistent with diagnosis of hypophosphatasia AND Physical examination findings consistent with a diagnosis of hypophosphatasia AND Presence of low serum alkaline phosphatase level for age and sex AND Elevation of at least one natural substrate of alkaline phosphatase Lack of detection of a variant on molecular analysis of the ALPL gene. When possible, first degree relatives (parents, siblings, or child) will be included for the sole purpose of trio testing. No additional information will be collected on first degree relatives.  Aim 2-  Missense variant in ALPL which is interpreted as a variant of uncertain significance by the American College of Medical Genetics Guidelines for Variant Interpretation Variant has been interpreted as pathogenic, likely pathogenic, likely benign, or benign using ex-US interpretation guidelines  Exclusion Criteria:  Aim 1-  History and physical examination incompatible with a diagnosis of hypophosphatasia OR Absence of hypophosphatasemia as measured by age and sex-matched control OR Absence of at least one elevated natural substrate of alkaline phosphatase OR Alternate diagnosis which could overlap with signs and symptoms of hypophosphatasia  Aim 2-  1. Inability to express variant in plasmid for residual enzyme and co-transfection analyses