E824K
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 824 in lumenal domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.566 (borderline), ΔΔG -0.13.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | W700 | W700 | Preserved |
| Hydrogen bond | I845 | I845 | Preserved |
| Hydrogen bond | S846 | S846 | Preserved |
| Polar contact | W700 | W700 | Preserved |
| Polar contact | I845 | I845 | Preserved |
| Polar contact | S846 | S846 | Preserved |
| Carbonyl | I845 | I845 | Preserved |
| Hydrophobic | T701 | T701 | Preserved |
| Hydrophobic | L848 | L848 | 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
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 at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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.
Highest in European (non-Finnish): AF 0.0064% (75 of 1,173,986 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) | 0.0064% | 75 / 1,173,986 | 0 | ~1 in 7830 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,042 | 0 | — |
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 824 in lumenal domain. Neighbors: PHE825 (2.4 Å — W700-F825 π-stacking partner!), ILE823 (2.5 Å), TRP700 (3.5 Å — direct contact with W700 Cat 2 region!), SER846 (3.7 Å).
E824 sits in direct contact with W700 and F825 — the same aromatic cluster identified in W700C and T699P Atlas cards. The wild-type E824 negative charge contributes to this microregion. Charge-flipping to K824 disrupts the local environment supporting W700-F825 π-stacking.
Mild ΔΔG; AM 0.566 borderline + DFNA6 confirm severe consequence.
Druggability Assessment
Mechanism: charge-flip in the W700-F825 aromatic cluster. Therapeutic: same W700-F825 microregion (with W700S/C, T699P/M).
Why this matters
Feed this card to Wolfram Intelligence
Download the E824K 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.