G736R
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Arginine at position 736 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.984, DynaMut2 ΔΔG -0.92 kcal/mol (destabilising). Another glycine-removal variant — paralleling the G674 cluster mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | — | E717 | Gained |
| Hydrogen bond | — | E717 | Gained |
| Hydrogen bond | R732 | R732 | Preserved |
| Polar contact | — | E717 | Gained |
| Polar contact | R732 | R732 | Preserved |
| Polar contact | — | C765 | Gained |
| Polar contact | H766 | H766 | Preserved |
| Carbonyl | — | R732 | Gained |
| Carbonyl | — | C733 | Gained |
| Carbonyl | H766 | H766 | Preserved |
| Van der Waals | — | R732 | Gained |
| Van der Waals | H766 | H766 | Preserved |
| Hydrophobic | — | R732 | Gained |
| Hydrophobic | — | I767 | Gained |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 736 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G736 within 5 Å of GLU737 (2.4 Å), TYR735 (2.5 Å), ARG732 (3.1 Å — a four-residue-back contact), HIS766 (3.3 Å — long-range), and ILE767 (4.1 Å). The local environment combines polar (E737, Y735), basic (R732), and titratable (H766) residues with a hydrophobic contact (I767).
The wild-type glycine at 736 plays the same backbone-flexibility role described for the G674 cluster. The neighbor analysis shows particularly tight packing — multiple residues within 4 Å — suggesting the local fold is geometrically constrained, and glycine's lack of side chain is what enables that geometry. Notably, ARG732 sits 3.1 Å away; the wild-type G736 plus R732 form a tight cluster where a single basic residue dominates the local electrostatic character.
Replacing glycine with arginine adds a second positive charge at 3.1 Å from the existing R732. This produces a two-arginine cluster similar to the G674R case — local electrostatic repulsion between adjacent positive charges plus the loss of glycine's backbone flexibility.
The |ΔΔG| of 0.92 reflects this combined cost. AlphaMissense's 0.984 score captures the severe functional consequence — likely disruption of a specific lumenal interaction surface where R732 alone served as the recognized positive charge.
Druggability Assessment
The mechanism is loss of glycine flexibility plus introduction of a second positive charge adjacent to R732 — disrupting a likely partner-recognition surface where R732 alone was the wild-type signature.
Therapeutic strategy: site-directed small molecules at the R732-G736-Y735 microregion. Pharmacological chaperones biasing the local backbone toward the wild-type glycine-enabled geometry.
Why this matters
Feed this card to Wolfram Intelligence
Download the G736R PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.