By profiling the genetic and phenotypic diversity associated with AATD through GP-SCV principled relationships in response to the ATPase inhibitor PU-WS13, we uncovered unexpected and precision residue–residue coupled relationships that simultaneously correct the defects in polymer formation, monomer folding, secretion, and NE inhibitory activity of most pathogenic AAT variants. This evidence concerns the gene SERPINA1 and alpha 1-antitrypsin deficiency.