E169K
Category 3/4 — Most DruggablePathogenic/Likely pathogenicCytoplasmic · predictedEditorialGlutamate → Lysine at position 169 in wolframin's N-terminal cytoplasmic domain. ClinVar Pathogenic/Likely pathogenic across both AD and AR WFS1-related disorders. AlphaMissense 0.948, DynaMut2 ΔΔG -0.39 kcal/mol (destabilising). A clean charge-flip variant with documented dual-inheritance impact.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R177 | — | Lost |
| Ionic bond | K252 | — | Lost |
| Hydrogen bond | Q165 | Q165 | Preserved |
| Hydrogen bond | L166 | L166 | Preserved |
| Hydrogen bond | E173 | E173 | Preserved |
| Hydrogen bond | R174 | R174 | Preserved |
| Hydrogen bond | K252 | — | Lost |
| Polar contact | Q165 | Q165 | Preserved |
| Polar contact | — | E173 | Gained |
| Polar contact | R174 | R174 | Preserved |
| Polar contact | R177 | — | Lost |
| Polar contact | K252 | — | Lost |
| Van der Waals | S167 | — | Lost |
| Van der Waals | — | E173 | Gained |
| Van der Waals | — | R174 | Gained |
| Van der Waals | R177 | — | Lost |
| Hydrophobic | E173 | E173 | Preserved |
| Hydrophobic | — | K252 | Gained |
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 Pathogenic/Likely pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Optic atrophy / optic neuropathy (autosomal dominant). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: Autosomal dominant and autosomal recessive WFS1-related disorders
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic neuropathy
- 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.
Highest in Remaining individuals: AF 0.0096% (6 of 62,478 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. |
|---|---|---|---|---|
| Remaining individuals | 0.0096% | 6 / 62,478 | 0 | ~1 in 5210 |
| European (non-Finnish) | 0.0059% | 70 / 1,180,034 | 0 | ~1 in 8430 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,606 | 0 | — |
| East Asian · under-sampled | 0.0022% | 1 / 44,872 | 0 | — |
| Admixed American · under-sampled | 0.0017% | 1 / 60,002 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,884 | 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 169 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places E169 within 5 Å of THR170 (2.4 Å), SER168 (2.5 Å), GLU173 (3.9 Å), LEU166 (4.2 Å), and GLN165 (4.2 Å). The local environment is polar-leaning, with a nearby second glutamate (E173) suggesting the wild-type E169 may contribute to a charged surface patch.
Replacing glutamate with lysine here reverses the charge sign at this position. Where the wild-type contributed a negative charge to the local electrostatic environment, the mutant contributes a positive one. The two glutamate residues E169 and E173 may have been forming a negatively-charged cytoplasmic surface patch — a recognition signature for a partner protein with a complementary positively-charged surface. Flipping E169 to lysine destroys that recognition surface and replaces it with one of opposite character.
The |ΔΔG| of 0.39 kcal/mol is modest because the fold itself accommodates the charge-flip — both glutamate and lysine are flexible polar residues. The structural cost is minor. But the functional cost — disrupted electrostatic recognition surface for partner proteins — is severe, captured by AlphaMissense's 0.948 score and the documented dual-inheritance clinical impact.
Druggability Assessment
The mechanism is charge-sign reversal at a cytoplasmic recognition surface. The lost negative charge plus the new positive charge together disrupt whatever partner-protein recognition the wild-type E169/E173 patch enabled.
Therapeutic strategy: this is a functional-site disruption rather than a fold problem. Site-directed small-molecule design at the recognition surface — restoring or compensating for the lost negatively-charged patch — is the rational vector. Alternatively, if the disrupted recognition target can be identified, indirect rescue via the partner protein.
Why this matters
Feed this card to Wolfram Intelligence
Download the E169K 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.