E301K

Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorial

Glutamate → Lysine at position 301 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Glutamate → Lysine at position 301 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.757, ΔΔG -0.63. Charge-flip variant.

Interactive 3D Structure

Wild-type reference

Wild-type E301 — hydrogen bond to E298

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DynaMut2 mutant · E301K

Mutant K301 — hydrogen bond contact to I304 lost

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M297	M297	Preserved
Hydrogen bond	E298	E298	Preserved
Hydrogen bond	I304	I304	Preserved
Hydrogen bond	D305	D305	Preserved
Polar contact	M297	M297	Preserved
Polar contact	E298	E298	Preserved
Polar contact	—	I299	Gained
Polar contact	I304	I304	Preserved
Polar contact	D305	D305	Preserved
Van der Waals	I299	I299	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

-0.63kcal/mol

Destabilising — mild

AlphaMissense

0.757

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 conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.901G>A

ClinVar accessionVCV000591065

Last evaluated2025/09/20 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

Position 301 in cytoplasmic domain. Neighbors: TYR302 (2.5 Å), LYS300 (2.5 Å — adjacent existing lysine!), GLU298 (3.6 Å), MET297 (3.8 Å).

E301K creates two adjacent positives (K300-K301) where wild-type had K300-E301 alternating. The E298 partner of wild-type E301 loses one of its like-charged neighbors. ΔΔG 0.63 + AM 0.757 + Wolfram 1 confirm severe consequence.

Amino-acid chemistry

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

Position in the protein

N-terminal cytoplasmic domain · position 301 (pLDDT 73).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.63. AlphaMissense 0.757 + Wolfram 1 confirm severe consequence.

Mechanism: charge-flip creating adjacent two-lysine cluster. Therapeutic: site-directed at the 298-302 microregion.

Why this matters

E301K joins the charge-flip class. The 298-302 region has a deliberate alternating positive-negative pattern that the variant disrupts.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E301K 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 E301K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A