G831D
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialGlycine → Aspartate at position 831 in wolframin's C-terminal lumenal domain. ClinVar Conflicting. AlphaMissense 0.923, ΔΔG -0.85. Glycine-removal with charge introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L833 | L833 | Preserved |
| Polar contact | L833 | L833 | Preserved |
| Van der Waals | 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 831 sits in the lumenal domain. Neighbors: ARG832 (2.5 Å — likely salt-bridge partner with new D831!), GLU830 (2.5 Å — adjacent existing carboxylate), LEU833 (4.7 Å), GLU694 (4.8 Å — long-range).
Replacing G831 with aspartate creates a charge cluster: the new D831 carboxylate plus the existing E830, with R832 nearby as potential bridge. The local backbone flexibility is lost; the local electrostatic environment is transformed.
The |ΔΔG| of 0.85 reflects substantial fold cost. AlphaMissense 0.923 confirms severe consequence.
Druggability Assessment
Mechanism: glycine-removal plus charge introduction at the R832-E830 electrostatic environment. Therapeutic: site-directed at the 830-832 microregion.
Why this matters
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