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This method classifies variants into different groups based on variant annotations (pLOF, all missense, missense (1/5), missense (5/5)) and allele frequency thresholds (1%, 0.05%, 0.01%, 0.001%, and singletons) and applies four main testing strategies: BURDEN (classic burden test across allele frequency bins), SBAT (Set-Based Association Test assuming same effect direction), SKATO (Sequence Kernel Association Test Optimal for mixed effect directions), and ACATV (Aggregated Cauchy Association Test for Variants)