K252E
Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorialLysine → Glutamate at position 252 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.872, ΔΔG -1.26. Charge-flip variant in cytoplasmic domain.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E169 | — | Lost |
| Ionic bond | E249 | — | Lost |
| Ionic bond | — | K256 | Gained |
| Hydrogen bond | E169 | — | Lost |
| Hydrogen bond | V248 | V248 | Preserved |
| Hydrogen bond | E249 | E249 | Preserved |
| Hydrogen bond | A255 | A255 | Preserved |
| Hydrogen bond | K256 | K256 | Preserved |
| Polar contact | E169 | — | Lost |
| Polar contact | V248 | V248 | Preserved |
| Polar contact | E249 | E249 | Preserved |
| Polar contact | I250 | I250 | Preserved |
| Polar contact | Y254 | — | Lost |
| Polar contact | A255 | A255 | Preserved |
| Polar contact | K256 | K256 | Preserved |
| Van der Waals | V248 | — | Lost |
| Van der Waals | I250 | I250 | Preserved |
| Van der Waals | Y254 | — | Lost |
| Hydrophobic | E173 | E173 | Preserved |
| Hydrophobic | V176 | — | 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 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
- 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 252 sits in cytoplasmic domain. Neighbors: LYS253 (2.5 Å — adjacent existing lysine!), THR251 (2.5 Å), GLU249 (3.7 Å — likely salt-bridge partner with wild-type K252), VAL248 (3.7 Å).
Replacing K252 with glutamate creates two negative charges (new E252 + existing E249) where wild-type had a positive K252 + negative E249 salt bridge. The local electrostatic surface flips polarity. |ΔΔG| 1.26 reflects substantial cost. AlphaMissense 0.872 + Wolfram 1 confirm severe consequence.
Druggability Assessment
Mechanism: charge-flip disrupting K252-E249 salt bridge + creating two-glutamate cluster. Therapeutic: site-directed at the 249-253 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the K252E 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.