Expanding the global knowledge base for HPP beyond ClinVar and other public resources.
A 158% increase in actionable yield versus ClinVar alone.
A total of 391 actionable variants, including 143 concordant with clinical labs.
Evidence made freely available in ClinVar and Mastermind to ensure global visibility and consistent use across labs.
Hypophosphatasia (HPP) is a rare genetic metabolic disorder caused by mutations in the ALPL gene, which impair the tissue non-specific alkaline phosphatase (TNSALP) enzyme. This results in poor bone mineralization, leading to skeletal deformities, fractures, and systemic complications.
Diagnosis is often delayed:
• Many ALPL variants were missing or underrepresented in ClinVar.
• Inconsistent classifications limited diagnostic confidence across laboratories.
• A high rate of variants of uncertain significance (VUS) slowed patient identification and care.
Alexion, developer of STRENSIQ® (asfotase alfa) — the first targeted enzyme replacement therapy for HPP — sought to expand disease awareness and shorten time-to-diagnosis by ensuring that every literature-supported ALPL variant and its evidence could be found, trusted, and used by the global community.
Extract literature-driven real-world evidence
Genomenon applied its AI-powered platform and expert scientific review to scan the biomedical literature and curate all ALPL variants according to ACMG/AMP guidelines.
Build the ALPL variant knowledgebase
2021 curation: 477 variants identified, including 300 published variants absent from Clinvar.
• 4sc 286 actionable variants, with 200 unique pathogenic/likely pathogenic variants not in ClinVar — a 330% increase in actionable yield.
2025 reanalysis and update: 514 curated variants submitted to ClinVar.
• 123 variants not previously in ClinVar.
• 391 actionable variants (a 26.9% increase from original curation).
• 248 unique pathogenic/likely pathogenic variants compared to ClinVar.
• 143 concordant variants with other clinical labs — a 166% increase in clinical submissions.
Share the results with the world
All curated variants and supporting evidence were made freely available in Genomenon’s Mastermind Genomic Intelligence Platform and submitted to ClinVar, ensuring global access and consistency in interpretation.
Maintain a living knowledgebase
Annual updates ensure new findings and reclassifications are continuously incorporated, keeping the ALPL dataset current and actionable.
Improved diagnostic confidence: More accurate and consistent interpretation of ALPL variants reduces diagnostic uncertainty.
Global knowledge sharing: Open access in ClinVar and Mastermind empowers clinicians and researchers worldwide.
Consistent lab interpretation: Standardized, reference-backed evidence reduces variability across testing laboratories.
Sustained awareness: Ongoing updates ensure the knowledgebase remains current and continues to drive earlier, more accurate diagnosis.
Expanded patient access: By increasing the number of actionable variants tied to clinical utility, more patients can be identified as eligible for STRENSIQ® treatment.
Genetic Disease Sponsorship enables biopharma partners to promote awareness and increase diagnostic rates by underwriting the creation, curation, and public distribution of a comprehensive, literature-driven variant knowledgebase. This resource is kept current over time and made accessible globally to clinicians and researchers.
We help provide insights into key genetic drivers of diseases and relevant biomarkers. By working together to understand this data, we enable scientists and researchers to make more informed decisions on programs of interest. To learn more about how we can partner together to find your genomic variant solutions, we invite you to click on the link below.
