E394V

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Glutamate → Valine at position 394 · Connecting loop · WFS1 (Wolframin)

Glutamate → Valine at position 394 in a connecting loop. ClinVar Conflicting including spastic ataxia and DFNA6. AlphaMissense 0.917, ΔΔG +1.18 STABILISING.

Interactive 3D Structure

Wild-type reference

Wild-type E394 — ionic bond to R375

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DynaMut2 mutant · E394V

Mutant V394 — ionic bond to R522 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost0 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	R375	—	Lost
Ionic bond	R522	—	Lost
Hydrogen bond	R375	—	Lost
Hydrogen bond	V390	V390	Preserved
Hydrogen bond	E391	E391	Preserved
Hydrogen bond	F397	F397	Preserved
Hydrogen bond	G398	G398	Preserved
Hydrogen bond	R522	—	Lost
Polar contact	R375	—	Lost
Polar contact	V390	V390	Preserved
Polar contact	E391	E391	Preserved
Polar contact	F397	F397	Preserved
Polar contact	G398	G398	Preserved
Polar contact	R522	—	Lost
Van der Waals	W371	—	Lost
Hydrophobic	W371	W371	Preserved
Hydrophobic	F374	F374	Preserved
Hydrophobic	V390	V390	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

DynaMut2 ΔΔG

1.18kcal/mol

Stabilising — moderate

AlphaMissense

0.917

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsSpastic ataxia; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceSpastic ataxia and DFNA6 documented.

Population frequency (gnomAD v4)Low frequency · AF 0.013%

cDNA changec.1181A>T

ClinVar accessionVCV000546078

Last evaluated2026/01/26 00:00

Observed in the general population.

Structural Context

Position 394 sits in a connecting loop. Neighbors: VAL395 (2.5 Å), ALA393 (2.5 Å), VAL390 (3.8 Å), GLU391 (3.8 Å — second nearby glutamate).

The wild-type E394 with nearby E391 forms a charge cluster in this loop. Replacing E394 with valine eliminates one of two negative charges; the variant fold packs more efficiently with valine in the surrounding hydrophobic environment (V395, V390, A393), producing stabilising ΔΔG of +1.18.

Yet AlphaMissense 0.917 + spastic ataxia + DFNA6 clinical evidence confirm severe consequence. The mechanism is loss of the negatively-charged surface that the wild-type E394 contributed to — partner-recognition disruption despite structural gain.

Amino-acid chemistry

Glutamate (E) → Valine (V) — negatively-charged carboxylate replaced by branched aliphatic hydrophobic. Complete charge loss in a polar environment.

Position in the protein

Connecting loop · position 394 (pLDDT 82).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG = +1.18 stabilising. AlphaMissense 0.917 + multi-phenotype confirm severe consequence.

Mechanism: loss of E394 charge from the local surface patch. Therapeutic: recognition-surface site-directed.

Why this matters

E394V joins the growing stabilising-but-pathogenic class. Pattern is consistent: charge-loss variants where fold tightens but partner recognition fails.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E394V 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 E394V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin