E864K
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialCharge-flip mutation at the very C-terminal edge of the lumenal domain — glutamate's negative carboxylate replaced by lysine's positive amine, in a region where pLDDT (59) signals borderline confidence and the structural interpretation requires explicit caution.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R697 | — | Lost |
| Ionic bond | K862 | — | Lost |
| Hydrogen bond | R697 | — | Lost |
| Hydrogen bond | K862 | K862 | Preserved |
| Hydrogen bond | D866 | D866 | Preserved |
| Polar contact | R697 | — | Lost |
| Polar contact | K862 | — | Lost |
| Polar contact | D866 | D866 | Preserved |
| Van der Waals | — | D866 | Gained |
| Hydrophobic | K843 | — | Lost |
| Hydrophobic | K862 | K862 | Preserved |
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 59.28 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 Pathogenic/Likely pathogenic for Hearing loss, inheritance unstated (inheritance not specified); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Retinal dystrophy (inheritance not specified); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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.
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness; Nonsyndromic genetic hearing loss
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss; Autosomal dominant nonsyndromic hearing loss 6
- Retinal dystrophyinheritance not specifiedsubmitted as: Retinal dystrophy
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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: 2★ multiple submitters, no conflicts. 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
E864 has only four neighbors within 5 Angstrom: His865 (2.41 Angstrom), Ile863 (2.43 Angstrom), Asp866 (4.75 Angstrom), and Lys862 (4.80 Angstrom). The minimal contact set is itself diagnostic — at pLDDT 59, AlphaFold is signaling that the local conformation is partially ordered or solvent-exposed rather than packed against a stable core. The neighborhood is locally informative nonetheless: a histidine, a downstream aspartate, and an upstream lysine all sit within the polar shell.
In the wild-type configuration, E864's carboxylate plausibly forms a salt bridge with K862 (4.80 Angstrom is within typical salt-bridge range when sidechain conformations are accounted for), and may hydrogen-bond to His865 depending on the imidazole's protonation state. The downstream Asp866 contributes additional negative charge to the local cluster — two glutamates/aspartates and one lysine, balanced.
E864K flips the charge sign on E864. The K862-E864 salt bridge is destroyed because both residues are now positively charged — they will electrostatically repel rather than attract. The local cluster goes from -E864 ... +K862 ... -D866 (a balanced charge triad) to +K864 ... +K862 ... -D866 (a positive pair next to a negative residue). The geometric consequence is that K862 and K864 likely splay apart, dragging the backbone with them, while D866's carboxylate may rotate to form a new salt bridge with one of the lysines.
DynaMut2's DeltaDeltaG of -0.26 kcal/mol substantially under-reads the disruption — energy functions tend to compensate the electrostatic loss when a new contact forms, even if that contact is geometrically forced. AlphaMissense at 0.842 reads the true severity. The clinical phenotype is broad: retinal dystrophy, autosomal dominant nonsyndromic hearing loss 6, Wolfram-like syndrome — consistent with a C-terminal lumenal disruption affecting the function of the lumenal sensor face.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the E864K 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.