Defects in proteostasis are the underlying cause of disease in a wide range of inherited disorders. Misfolding of mutant Human ether-á-go-go related gene (hERG, Kv11.1) potassium channels, results in congenital long QT syndrome type 2, one of the commonest causes of sudden cardiac death in the young. Pharmacological rescue of the underlying trafficking defect is a very attractive management goal in this condition. Drugs that bind in the central cavity of the mature channel can overcome the trafficking defect in some but not all mutant channels. To explore the mechanistic basis of the variability in drug response we have quantified the folding, trafficking defects and pharmacological rescue of mutations in the cytosolic PAS domain of hERG, a hotspot for mutations that have a moderately severe clinical phenotype. Mutations in a surface exposed hydrophobic patch on the PAS domain affect domain-domain interactions and are only poorly rescued, whilst the rescue of other mutant channels is directly proportional to the severity of misfolding of the PAS domain. Our results demonstrate a critical role for the PAS domain in hERG channel biogenesis, in addition to its role in regulating channel function. Further, PAS domain interactions with the remainder of the channel are critical for pharmacological stabilization of trafficking defective mutants.