E717K
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 717 in lumenal domain. ClinVar Conflicting with broad clinical spectrum — Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome. AlphaMissense 0.36 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.18 kcal/mol (mild destabilising). Charge-flip adjacent to the N714 polar network.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | K768 | — | Lost |
| Hydrogen bond | N714 | N714 | Preserved |
| Hydrogen bond | N721 | N721 | Preserved |
| Hydrogen bond | K768 | — | Lost |
| Polar contact | N714 | N714 | Preserved |
| Polar contact | A719 | A719 | Preserved |
| Polar contact | I720 | I720 | Preserved |
| Polar contact | N721 | N721 | Preserved |
| Polar contact | K768 | — | Lost |
| Van der Waals | N714 | N714 | Preserved |
| Van der Waals | A719 | A719 | Preserved |
| Hydrophobic | N714 | N714 | Preserved |
| Hydrophobic | I767 | I767 | 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 Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). 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.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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
- 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 Remaining individuals: AF 0.0064% (4 of 62,468 alleles), 2.1x the global figure. The global AF describes the general population, not the at-risk group.
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 | 0.0064% | 4 / 62,468 | 0 | ~1 in 7810 |
| Admixed American | 0.0050% | 3 / 59,982 | 0 | ~1 in 10000 |
| European (non-Finnish) | 0.0035% | 41 / 1,179,938 | 0 | ~1 in 14390 |
| East Asian · under-sampled | 0.0022% | 1 / 44,880 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,940 | 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 717 sits in wolframin's C-terminal lumenal domain. Neighbors: SER718 (2.5 Å), ALA716 (2.5 Å — adjacent to N714 cluster), ASN714 (3.8 Å — the N714T/N714S/N714K position!). The N714 contact at 3.8 Å places E717 in direct structural proximity to the densest multi-variant target in the Atlas (the D713-N714-D771-K768 polar network).
The wild-type E717 likely contributes negative charge to the polar network surrounding N714. Replacing E717 with lysine reverses the charge sign — the network now has K717 + the existing K768 plus N714's amide where the wild-type had E717 + N714.
The |ΔΔG| of 0.18 is mild. AlphaMissense's 0.36 is below threshold (AM under-call). The broad clinical spectrum (three phenotypes: Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome) plus the structural mechanism confirm pathogenicity.
Druggability Assessment
Mechanism: charge-flip immediately adjacent to the N714 polar network. Therapeutic strategy: same D713-N714-D771-K768 microregion as N714T/S/K, D771H, D771Y.
Why this matters
Feed this card to Wolfram Intelligence
Download the E717K 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.