Reframing SERPING1 Variants of Uncertain Significance in Hereditary Angioedema: a dynamic threshold-based conceptual framework

Variants of uncertain significance (VUS) in SERPING1 represent a persistent challenge in the clinical interpretation of hereditary angioedema (HAE). Current classification approaches often treat SERPING1 dysfunction as a binary phenomenon, insufficiently accounting for the dynamic regulation of the kallikrein–bradykinin pathway. Here, we propose a threshold-based conceptual model in which SERPING1 variants may act as subclinical destabilizers within a metastable regulatory system, contributing to variable clinical expressivity without producing overt loss of function. This work does not provide clinical reclassification of VUS nor functional validation. Rather, it offers a mechanistic lens to reinterpret genetic ambiguity in HAE and to guide hypothesis generation and experimental prioritization.