CFTR and cystic fibrosis: Using Gaussian process (GP)-based machine learning with 71 variants triggering CF in the population4, we recently demonstrated1–7,145 the existence of a thermodynamically sensitive region of the CFTR fold involving the interfaces between nucleotide binding domain 1 (NBD1) contributed by the F508 and R560 residues, and the fourth intracellular loop 4 (ICL4) of transmembrane (TM) domain 2 (TMD2), the latter being responsible for COPII engagement for trafficking from the ER via the di-acidic exit motif3,4.