In IgG1, the stable interaction of the two heavy chains results from the combined effects of stable covalent inter H‐chain disulfide bonds and strong noncovalent interaction of the two CH3 domains (Table 3). In stark contrast, in IgG2 and IgG4 the interaction of the CH3 domains of each H‐chain is weak. Residues 392, 397 and 409 (Eu numbering) profoundly affect the stability of these interactions. The difference at position 409 (R409 in IgG4 and K409 in IgG1) confers a 100‐fold decrease in stability of the interface between the two CH3 domains of IgG4 compared with that of IgG1 (Table 3).69