This overview highlights the significant role of genetic variability in human tryptases, particularly focusing on hereditary alpha-tryptasemia (HαT), and its impact on mast cell-mediated reactions and associated clinical phenotypes. HαT is linked to clonal mast cell disorders (MCD) and is associated with increased instances of anaphylaxis, including idiopathic anaphylaxis and severe reactions to Hymenoptera venom. Furthermore, even without HαT, a higher number of α-tryptase-encoding gene copies correlates with systemic mastocytosis severity and heightened sensitivity to vibration and food. This sensitivity is attributed to the enhanced production of α/β-tryptase heterotetramers, which differ in enzymatic activity from β-tryptase homotetramers. Essentially, HαT acts as a model for α-tryptase overexpression in humans, modifying immediate hypersensitivity symptoms and leading to more frequent and severe mast cell-mediated reactions due to increased α/β-tryptase heterotetramer production. This research underscores the importance of genetic factors in understanding and managing allergic and hypersensitivity conditions.