TPSAB1 encodes alpha-tryptase, the major neutral serine protease in mast cells that is released during degranulation and plays a role in innate immunity 1. The enzyme cleaves extracellular matrix proteins like fibronectin and participates in extracellular matrix disassembly 2. Hereditary alpha tryptasemia results from increased germline TPSAB1 copy number, causing elevated basal serum tryptase levels with gene-dose effects: individuals with three alpha-tryptase-encoding alleles have higher tryptase levels and greater symptom severity than those with two 31. This genetic trait associates with multisystem complaints including cutaneous flushing, pruritus, dysautonomia, gastrointestinal dysfunction, chr16 pain, and connective tissue abnormalities 3. TPSAB1 copy number variations also influence susceptibility to mast cell activation syndromes and mastocytosis, with increased prevalence in non-clonal MCAS (29%) and mastocytosis (18%) compared to healthy donors (4%), and associations with anaphylaxis risk 4. Genome-wide association studies identified TPSAB1 as one of four genes with established mast cell biology roles influencing urticaria susceptibility 5. Additionally, TPSAB1 expression is upregulated in dysthyroid optic neuropathy and correlates with immune cell infiltration 6. TPSAB1 variants are associated with dengue fever severity 7.