E794K

Category 5 — IDR ExclusionConflictingLumenal · predictedσ-1 candidateEditorial

Glutamate → Lysine at position 794 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Glutamate → Lysine at position 794 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.24 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.49 STABILISING. pLDDT 49 — Category 5 IDR boundary!

Interactive 3D Structure

Wild-type reference

Wild-type E794 — ionic bond to K800

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DynaMut2 mutant · E794K

Mutant K794 — ionic bond to K800 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K800	—	Lost
Hydrogen bond	S792	S792	Preserved
Hydrogen bond	D797	D797	Preserved
Hydrogen bond	K800	K800	Preserved
Polar contact	S792	S792	Preserved
Polar contact	D796	D796	Preserved
Polar contact	D797	D797	Preserved
Polar contact	K800	—	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

DynaMut2 ΔΔG

0.49kcal/mol

Stabilising — mild

AlphaMissense

0.242

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 5

Category 5 — IDR Exclusion

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Low frequency · AF 0.017%

cDNA changec.2380G>A

ClinVar accessionVCV000198836

Last evaluated2026/01/26 00:00

Observed in the general population.

Structural Context

Position 794 at pLDDT 49 — RIGHT AT the Category 5 IDR threshold. Computational predictions deserve caution. Neighbors: GLU795 (2.5 Å), ARG793 (2.5 Å), SER792 (3.8 Å).

E794K charge-flips in a borderline IDR region. ΔΔG predictions not trustworthy here. AM 0.24 below threshold but Wolfram 1 documented.

Amino-acid chemistry

Glutamate (E) → Lysine (K) — charge reversal.

Position in the protein

C-terminal lumenal domain · position 794 (pLDDT 49 — IDR boundary).

Druggability Assessment

Category 5 — IDR Exclusion (borderline). pLDDT 49 at the 50 threshold. AlphaMissense 0.24 below threshold. Multiple signals suggest computational caution.

The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery.

Why this matters

E794K is another borderline IDR variant — Atlas appropriately flags for wet-lab work.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E794K 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.

Download E794K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal