Systematic and proactive evaluation of AIRE missense variant effects.

Proactive assessment of 9,790 AIRE missense variants enables rapid classification, resolving 32% of uncertain cases and improving diagnosis of autoimmune polyendocrine syndrome type 1.

• Why it matters: Accurate and early diagnosis of APS-1 is crucial for effective treatment, but over half of the clinical variants are of uncertain significance, delaying diagnosis and intervention.
• What they did: Using an insulin-promoter-driven reporter, the study systematically evaluated nearly 10,000 AIRE missense variants to create a comprehensive variant effect map that correlates with pathogenicity.
• The result: The map validated existing knowledge, extended variant classification, and provided evidence for 70% of previously uncertain variants, paving the way for faster, more definitive APS-1 diagnoses.