Although the impact of genome variation on the thermodynamic properties of the protein fold has been studied in vitro, it remains a challenge to assign these relationships across the entire polypeptide sequence in vivo. Using the Gaussian process regression-based principle of Spatial CoVariance (SCV), we globally assign on a residue-by-residue the biological thermodynamic properties contributing to the functional fold in the cell using CFTR as an example. We demonstrate the existence of a thermodynamically sensitive region of the CFTR fold involving the interface between NBD1 and ICL4 that contributes to the endoplasmic reticulum (ER) export. At the cell surface a new set of residues contribute uniquely to the management of channel function. These results support a general 'quality assurance' (QA) view of global protein fold management as an SCV principle describing the differential pre- and post-ER residue interactions contributing to compartmentalization of the energetics of the protein fold for function.