Brugada syndrome is usually interpreted through SCN5A genetics, yet many patients with a Brugada phenotype carry no clearly pathogenic SCN5A variant and penetrance among carriers is incomplete. Cardiac sodium-channel function is therefore not a direct readout of coding sequence but an integrated property shaped by the channelosome, transcriptional and epigenetic control, post-translational modification, metabolic state, and inflammatory signaling. Through these routes, oxidative stress, altered glycosylation, and Nedd4-2-dependent ubiquitination can reduce peak sodium current in experimental systems, potentially lowering conduction reserve; inflammatory mediators may additionally modify the regional substrate through other ionic pathways without altering the SCN5A coding sequence in the experimental system, converging on the loss-of-function phenotype that characterizes Brugada syndrome, in contrast to the late-current gain of function of long QT syndrome type 3. Epicardial adipose tissue may provide a regional context for such signals at the right ventricular outflow tract, where conduction reserve is low and the substrate preferentially localizes, and anti-Nav1.5 autoantibodies provide a humoral route to reduced channel availability. We examine sequence-independent modifiers that may dynamically reduce Nav1.5 function and define the experimental framework needed to establish their clinical weight.