D801G
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialAspartate → Glycine at position 801 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.985, DynaMut2 ΔΔG -0.26 kcal/mol (destabilising). The inverse mechanism of glycine-removal variants: here glycine is INTRODUCED into a position that previously carried a charge.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | K705 | — | Lost |
| Hydrogen bond | K705 | — | Lost |
| Hydrogen bond | V779 | V779 | Preserved |
| Hydrogen bond | G780 | — | Lost |
| Hydrogen bond | V798 | V798 | Preserved |
| Polar contact | K705 | — | Lost |
| Polar contact | V779 | V779 | Preserved |
| Polar contact | G780 | — | Lost |
| Polar contact | V798 | V798 | Preserved |
| Van der Waals | K705 | — | Lost |
| Hydrophobic | T778 | — | Lost |
| Hydrophobic | W837 | — | Lost |
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 801 sits in wolframin's C-terminal lumenal domain near the C-terminus. The AlphaFold model places D801 within 5 Å of ILE802 (2.4 Å), LYS800 (2.5 Å), VAL779 (3.5 Å, longer-range), VAL798 (3.9 Å), and GLY780 (4.8 Å). Critically, LYS800 sits 2.5 Å from D801 — a salt-bridge distance. The wild-type D801 carboxylate and K800 amine form a likely intramolecular salt bridge stabilizing the local fold.
Replacing aspartate with glycine eliminates the negative charge and removes the side chain entirely. The K800-D801 salt bridge breaks. The local geometry that depends on that ionic contact rearranges, and the introduced glycine permits backbone conformations that the wild-type aspartate constrained.
The |ΔΔG| of 0.26 is modest — the fold absorbs the loss of a single salt bridge. But the functional consequence is severe: AlphaMissense 0.985 captures it. The lost salt bridge likely contributed to a specific lumenal geometry required for partner interactions or for the wolframin C-terminus to engage its target proteins.
Notably, VAL779 (3.5 Å) is the partner residue in the V779G atlas card (a Category 2 outlier). D801 and V779 are spatially close. Drug discovery aimed at the V779 region may also engage the D801 microenvironment.
Druggability Assessment
The mechanism is loss of the K800-D801 intramolecular salt bridge plus introduction of glycine backbone flexibility into a previously constrained position. Therapeutic strategy: site-directed small molecules that restore the K800-region electrostatic geometry the wild-type D801 carboxylate provided.
Spatial proximity to V779 (3.5 Å, see V779G atlas card) suggests this region of the C-terminus harbors multiple pathogenic variants. A drug aimed at the V779-D801 region could rescue multiple Atlas variants simultaneously.
Why this matters
Feed this card to Wolfram Intelligence
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