E158K

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Glutamate → Lysine at position 158 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Glutamate → Lysine at position 158 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1 + Cataract 41. AlphaMissense 0.378 (below threshold), ΔΔG +0.55 STABILISING.

Interactive 3D Structure

Wild-type reference

Wild-type E158 — polar contact to T156

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DynaMut2 mutant · E158K

Mutant K158 — van der waals contact to T156 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained1 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	T156	Gained
Polar contact	T156	T156	Preserved
Van der Waals	T156	—	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

0.55kcal/mol

Stabilising — mild

AlphaMissense

0.378

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram syndrome 1; Cataract 41

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0011%

cDNA changec.472G>A

ClinVar accessionVCV001404588

Last evaluated2025/05/02 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 158 in cytoplasmic domain. Neighbors: ASN159 (2.5 Å), SER157 (2.5 Å), THR156 (4.0 Å), GLU160 (4.6 Å — second nearby glutamate).

E158K reverses charge. The E158-E160 charged pair becomes K158-E160 alternating charges. Fold stabilises slightly. AM 0.378 under-call; Wolfram + Cataract confirm pathogenicity.

Amino-acid chemistry

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

Position in the protein

N-terminal cytoplasmic domain · position 158 (pLDDT 87).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, stabilising). ΔΔG +0.55. AlphaMissense 0.378 below threshold but multi-phenotype confirms.

Mechanism: charge-flip in E158-E160 pair. Therapeutic: cytoplasmic recognition surface.

Why this matters

E158K joins charge-flip class + AM-under-call class. Cytoplasmic recognition-surface disruption.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E158K 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 E158K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A