K705E
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialLysine → Glutamate at position 705 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Cataract 41. AlphaMissense 0.975, DynaMut2 ΔΔG -0.17 kcal/mol (mild destabilising). Charge-flip variant at the SAME position as K705N (Atlas card adjacent).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | D801 | — | Lost |
| Hydrogen bond | T778 | T778 | Preserved |
| Hydrogen bond | D801 | — | Lost |
| Hydrogen bond | — | Q819 | Gained |
| Polar contact | R703 | R703 | Preserved |
| Polar contact | T778 | T778 | Preserved |
| Polar contact | D801 | — | Lost |
| Polar contact | Q819 | Q819 | Preserved |
| Van der Waals | D801 | — | Lost |
| Van der Waals | — | Q819 | Gained |
| Hydrophobic | T778 | — | 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 Conflicting classifications of pathogenicity for Cataract 41 (autosomal dominant, OMIM 116400). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Submitters conflict on this classification (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★ 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 705 same neighbor environment as K705N: TYR706 (2.4 Å), PHE704 (2.5 Å), THR778 (3.6 Å), GLN819 (4.4 Å), ARG703 (4.5 Å).
K705E is the charge-flip variant complementing K705N (charge-neutral) at this position. Where the wild-type K705 made a long-range contact (likely cation-π or salt bridge) with residues across the fold, the variant E705 makes opposite-sign electrostatic contacts. The R703 neighbor at 4.5 Å — previously experiencing K705's same-sign positive charge — now experiences an opposite-sign attractive contact.
The |ΔΔG| of 0.17 is mild — fold accommodates the charge flip easily. AlphaMissense's 0.975 + Cataract 41 clinical evidence confirm severe functional consequence. The mechanism is charge-reversal at the long-range contact position that K705 supplied positive charge to.
Druggability Assessment
Mechanism is charge-flip at K705 disrupting long-range contacts (THR778, GLN819). Therapeutic strategy: same microregion as K705N.
Why this matters
Feed this card to Wolfram Intelligence
Download the K705E 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.