K800E
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialLysine → Glutamate at position 800 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.778, ΔΔG -0.40. pLDDT 72 borderline. Same K800-D801 salt-bridge pair as D801G.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E794 | — | Lost |
| Hydrogen bond | E794 | — | Lost |
| Hydrogen bond | D797 | D797 | Preserved |
| Polar contact | — | W666 | Gained |
| Polar contact | E794 | — | Lost |
| Polar contact | D797 | D797 | Preserved |
| Polar contact | V798 | V798 | Preserved |
| Hydrophobic | D797 | — | 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
Observed in the general population.
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 specified", "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 0.028% (333 of 1,179,658 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) | 0.028% | 333 / 1,179,658 | 0 | ~1 in 1770 |
| Remaining individuals | 0.014% | 9 / 62,482 | 0 | ~1 in 3470 |
| Admixed American | 0.012% | 7 / 60,004 | 0 | ~1 in 4290 |
| African / African American | 0.0040% | 3 / 75,070 | 0 | ~1 in 12510 |
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 800 sits adjacent to D801. Neighbors: ASP801 (2.5 Å — D801G Atlas card!), THR799 (2.5 Å), ASP797 (3.7 Å), VAL798 (4.3 Å).
The wild-type K800-D801 salt bridge (referenced in D801G Atlas card) breaks when K800 becomes E800: now TWO adjacent glutamates (E800, D801) with no positive charge to stabilize. The local electrostatic environment is transformed. ΔΔG 0.40 + AM 0.778 confirm severe consequence.
Druggability Assessment
Mechanism: K800-D801 salt bridge broken by charge-flip at K800. Therapeutic: same K800-D801 microregion as D801G.
Why this matters
Feed this card to Wolfram Intelligence
Download the K800E 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.