While this value is higher than that predicted for missense mutations in transmembrane domains of disease-associated proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and rhodopsin (1.5 and 1.9 kcal/mol, respectively), it is in line with those predicted for mutations in phenylalanine hydroxylase (PAH) associated with mild or severe forms of phenylketonuria (5.7 and 14.2 kcal/mol, respectively) [33, 34]. Here, PAH is linked to pulmonary arterial hypertension.