OMIM *171760
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Welcome to the ALPL gene variant database. This site has been compiled to provide up-to-date information about genetic variations of the ALPL gene responsible for hypophosphatasia.
The ALPL gene (also called TNSALP; ID:249; MIM 171760) is localized on chromosome 1p36.12 and encodes tissue nonspecific alkaline phosphatase (TNSALP). Pathogenic loss of function mutations in ALPL cause hypophosphatasia (HPP), a rare, multisystemic condition that decreases the mineralization of bones and teeth and causes early loss of baby teeth, muscle weakness, and joint pain. In its most severe, recessively inherited perinatal and infantile forms, when left untreated has a very high mortality. HPP is also associated with pulmonary hypoplasia with respiratory failure, vitamin B6 responsive seizures, failure to thrive, craniosynostosis, and severe rickets-like features. HPP can present or manifest at any age since the phenotypic spectrum is a continuum. Traditional classification into prenatal benign (ORPHA247638), perinatal lethal (ORPHA 247623), infantile (ORPHA 247651), childhood (ORPHA 247667), adult (ORPHA 247676) and odonto HPP (ORPHA 247685) is under debate. The prevalence of severe forms is low (estimated at 1/300,000 in Europe, 1/100,000 in North America), whereas less severe forms are more frequently observed (estimated at 1/6000 in Europe).
Low serum alkaline phosphatase (ALP) is a hallmark diagnostic feature of HPP. However, the condition requires genetic confirmation since ALP can be low for various reasons (Saraff et al. 2016, Riancho-Zarrabeitia et al. 2016).
The global HPP registry is collecting real-world data to capture the phenotypic spectrum, the natural course of the disease, and the response to enzyme replacement therapy with asfotase alfa. Other approaches, such as gene therapy, are currently being investigated (Högler & Seefried 2025). For more information on HPP, also consult Orphanet.
More than 480 ALPL variants have been identified which are responsible for the extraordinary clinical heterogeneity. A clear but imperfect genotype-phenotype correlation has been observed, suggesting that other genetic or environmental factors modulate the phenotype.
According to ACMG/AMP criteria, variants can be classified into benign (1), likely benign (2), unknown significance (3), likely pathogenic (4), and pathogenic (5). This database aims to assist physicians, geneticists, researchers, and anyone interested in HPP to retrieve the most detailed and up-to-date information on every ALPL variant described to date. We are committed to providing up-to-date, comprehensive information not just on ALPL variants but also all reported genotypes and associated spectrum of phenotypes.
Until January 2021, this site was hosted by the University of Versailles (Prof Etienne Mornet). Our new site at the Johannes Kepler University Linz, Austria (JKU) builds on this work and strives to provide continuously updated, detailed variant-specific data on ALPL genotypes and associated phenotypes, variant classification according to ACMG/AMP criteria, and in-vitro enzyme activity compared to wild type, as well as information on dominant negative effects.
All variants refer to the MANE Select ALPL transcript NM_000478.6.
Prof Wolfgang Högler leads a consortium of researchers, endocrinologists, osteologists, basic scientists, and geneticists. The consortium meets regularly to assess research results from in-vitro testing and re-classify variants. The Members are: Priya Kishnani; Catherine Rehder; Cheryl Rockman-Greenberg; Kathryn Dahir; Gabriel Martos-Moreno; Agnes Linglart; Keiichi Ozono; Eric Rush; Lothar Seefried; Guillermo del Angel; Gerald Webersinke; Theodora Malli; Josephine Tauer; Wolfgang Högler (Consortium Lead, JKU Linz, Austria).
Please refer to this publication when citing the use of the ALPL Gene Variant Database.
Our research lab at JKU Linz, Austria has the capacity and the funding (externally sponsored research agreement, Alexion Pharmaceuticals, Inc) to conduct functional testing of VUS submitted to us. Clinicians and geneticists are encouraged to report any new ALPL variant to this site and thereby assist us in keeping it complete and up-to-date.
For submission of new variants, please register here
We also accept new genotypes or new phenotypes for known variants in our database. Please submit to hppresearch@jku.at