C690R
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialCysteine → Arginine at position 690 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 1.000 — the maximum possible pathogenicity score — paired with DynaMut2 ΔΔG of -1.29 kcal/mol (destabilising). High pathogenic confidence with a fold-intact mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | L672 | Gained |
| Hydrogen bond | — | C673 | Gained |
| Hydrogen bond | T686 | T686 | Preserved |
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | L693 | L693 | Preserved |
| Polar contact | — | L672 | Gained |
| Polar contact | C673 | C673 | Preserved |
| Polar contact | T686 | T686 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | H692 | H692 | Preserved |
| Polar contact | L693 | L693 | Preserved |
| Polar contact | L833 | L833 | Preserved |
| Van der Waals | — | C673 | Gained |
| Van der Waals | — | T686 | Gained |
| Van der Waals | — | Q687 | Gained |
| Van der Waals | L833 | L833 | Preserved |
| Hydrophobic | C673 | C673 | Preserved |
| Hydrophobic | L833 | L833 | Preserved |
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 690 sits in wolframin's C-terminal lumenal domain (residues 653–869). The ER lumen is the cell's primary oxidative folding compartment, and cysteine residues in lumenal domains commonly form structural disulfide bonds that lock the fold. The AlphaFold model places C690 within 5 Å of: LEU689 (2.5 Å) and SER691 (2.5 Å) as immediate sequence neighbors, but critically, also within 3.8 Å of CYS673 — another cysteine in the same domain.
This proximity to CYS673 is the key structural observation. A 3.8 Å Cα-to-CA distance between two cysteines is consistent with — though not definitive proof of — a disulfide bond connecting these two residues (typical Cys-Cys disulfides span 4.5-6.5 Å between Cα atoms; AlphaFold's modeling of disulfides is approximate but the spatial relationship is informative). If C690 and C673 form a structural disulfide in the lumenal fold, the C690R substitution destroys that bond entirely. Arginine cannot replicate the covalent crosslink.
Additionally, the substitution introduces a large positively charged guanidinium group into a position that previously held a small thiol. The surrounding lumenal environment (THR686, GLN687, HIS692, ILE688, LEU833 all within 5 Å) is mostly polar to neutral; introducing a charge here will reorganize the local hydrogen-bond network and the local electrostatics.
The combined effect — disulfide loss plus charge introduction — produces |ΔΔG| of 1.29 kcal/mol. Notably modest given how disruptive the chemistry is, which suggests the fold has slack to absorb the perturbation, but the AlphaMissense score of 1.000 indicates the functional consequence is severe even if the global fold tolerates it.
Druggability Assessment
The mechanism is a broken specific interaction — likely a structural disulfide between C690 and C673 plus disrupted local electrostatics — rather than global unfolding. This is the highest-priority druggability profile in the Atlas. The therapeutic strategy is site-directed: small molecules that re-stabilize the disrupted C673-C690 region of the lumenal fold, or that compensate for the lost crosslink by occupying the resulting cavity. Pharmacological chaperone screening with the WFS1 lumenal domain in folded form is the natural starting assay.
Gene therapy is unnecessary and likely contraindicated: the protein is folding, the variant is producing a measurable functional defect at a defined site, and that site is the rational target.
Why this matters
Feed this card to Wolfram Intelligence
Download the C690R 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.