G702S

G702 is wedged into a dense lumenal core. Its immediate covalent neighbors Arg703 (2.44 Angstrom) and Thr701 (2.45 Angstrom) flank it; the through-space contacts read like a packed hydrophobic-polar cluster — Val779 (3.50 Angstrom), Gly780 (3.54 Angstrom), Pro782 (3.76 Angstrom), Ile823 (3.89 Angstrom), Met781 (4.06 Angstrom), Phe825 (4.42 Angstrom). The Gly702-Gly780 pairing across 3.5 Angstrom is structurally interesting: two glycines in close apposition usually means a turn or hairpin that requires both backbones to adopt unusual phi/psi angles unavailable to other residues.

Replacing G702 with serine eliminates that geometric license. Serine has a beta-carbon and a hydroxyl, both compatible with standard Ramachandran space but incompatible with the disallowed-region phi/psi values that glycine populates here. The local backbone is forced to find a new conformation, and because Arg703 is the immediate downstream neighbor, the rearrangement carries Arg703's guanidinium with it — almost certainly displacing whatever salt bridge or hydrogen bond Arg703 contributes to the lumenal contact network with Pro782, Met781, or the Phe825 ring.

DynaMut2 returns DeltaDeltaG = -1.25 kcal/mol — destabilising and on the upper edge of the mild bucket. AlphaMissense 0.944 reads this as clearly pathogenic. The combination is consistent with a residue whose evolutionary indispensability is purely geometric: glycine is conserved at 702 not for any chemical contribution it makes but for the backbone freedom it provides. Any other residue, even one as conservative as serine, breaks the hairpin.

Clinically, G702S is documented in Wolfram syndrome 1 and optic atrophy — phenotypes that fit a lumenal-domain perturbation interfering with the ATF6 unfolded protein response axis. The fold survives; the function does not.