D797V
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAspartate → Valine at position 797 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.876, ΔΔG +0.04 (neutral). pLDDT 65 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E794 | E794 | Preserved |
| Hydrogen bond | T799 | — | Lost |
| Hydrogen bond | K800 | K800 | Preserved |
| Polar contact | E794 | E794 | Preserved |
| Polar contact | T799 | T799 | Preserved |
| Polar contact | K800 | K800 | Preserved |
| Van der Waals | — | T799 | Gained |
| Hydrophobic | — | T799 | Gained |
| Hydrophobic | K800 | — | 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
- pLDDT 64.88 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
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.
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 797 sits in the lumenal C-terminal region. Neighbors: VAL798 (2.4 Å), ASP796 (2.4 Å — adjacent aspartate), GLU794 (4.2 Å), THR799 (4.3 Å).
Replacing D797 with valine eliminates the negative charge in a local charged cluster (D796, E794 nearby). Fold accommodates (ΔΔG essentially zero). AlphaMissense 0.876 confirms severe consequence. Same position as D797N — both pathogenic.
Druggability Assessment
Mechanism: charge loss from local D796-D797-E794 cluster. Therapeutic: site-directed at this charge cluster.
Why this matters
Feed this card to Wolfram Intelligence
Download the D797V 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.