As GRP94 has been shown to be involved in the ERAD of AAT variants45–47, a process that is controlled by ER mannosidase I (ERManI/Man1b1)104–109, particularly in infants of AATD patient population108, it is likely that GRP94 establishes a variable level of stringency we have referred to as a plasticity set-point1,20 that is defined by the activity of the resident co-chaperone regulators in each cell type, and in response to the environment and aging (Fig. 8). The gene discussed is SERPINA1; the disease is alpha 1-antitrypsin deficiency.