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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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
Download the D801G 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.