K862N
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialLysine → Asparagine at position 862 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.981, DynaMut2 ΔΔG -0.20 kcal/mol (mild destabilising). pLDDT 64 borderline. A charge-loss variant near the C-terminus.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E864 | — | Lost |
| Ionic bond | D866 | — | Lost |
| Hydrogen bond | K843 | K843 | Preserved |
| Hydrogen bond | E864 | — | Lost |
| Hydrogen bond | D866 | — | Lost |
| Polar contact | K843 | — | Lost |
| Polar contact | E864 | — | Lost |
| Polar contact | D866 | — | Lost |
| Hydrophobic | A844 | A844 | Preserved |
| Hydrophobic | E864 | — | 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 64.12 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 Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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 862 sits near the C-terminus of wolframin's lumenal domain. The AlphaFold model places K862 within 5 Å of ILE863 (2.5 Å), VAL861 (2.5 Å), LYS843 (3.5 Å — second nearby lysine), ALA844 (4.0 Å), and GLU864 (4.6 Å — partner of E864K Atlas card).
The wild-type lysine likely forms a long-range salt bridge with E864 or contributes positive charge to a C-terminal surface patch including K843. Replacing K862 with N862 eliminates the positive charge and shortens the side chain. The mild |ΔΔG| of 0.20 reflects fold accommodation; AlphaMissense's 0.981 + Wolfram syndrome 1 clinical evidence confirm severe functional consequence.
Notably E864K (Atlas card adjacent) and K862N together establish the K862-E864 microregion as having multiple pathogenic variants — drug discovery here has convergent rescue opportunities.
Druggability Assessment
The mechanism is C-terminal surface charge loss. Therapeutic strategy: site-directed at the K862-E864 microregion — same target region as E864K.
Why this matters
Feed this card to Wolfram Intelligence
Download the K862N 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.