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
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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity, 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00085% (10 of 1,174,140 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00085% | 10 / 1,174,140 | 0 | ~1 in 58710 |
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 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
Feed this card to Wolfram Intelligence
Download the G831D 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.