K252E

Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorial

Lysine → Glutamate at position 252 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Lysine → Glutamate at position 252 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.872, ΔΔG -1.26. Charge-flip variant in cytoplasmic domain.

Interactive 3D Structure

Wild-type reference

Wild-type K252 — ionic bond to E169

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DynaMut2 mutant · K252E

Mutant E252 — ionic bond to E169 lost (8 contacts lost)

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Bond changes · DynaMut2 interaction analysis

8 lost1 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E169	—	Lost
Ionic bond	E249	—	Lost
Ionic bond	—	K256	Gained
Hydrogen bond	E169	—	Lost
Hydrogen bond	V248	V248	Preserved
Hydrogen bond	E249	E249	Preserved
Hydrogen bond	A255	A255	Preserved
Hydrogen bond	K256	K256	Preserved
Polar contact	E169	—	Lost
Polar contact	V248	V248	Preserved
Polar contact	E249	E249	Preserved
Polar contact	I250	I250	Preserved
Polar contact	Y254	—	Lost
Polar contact	A255	A255	Preserved
Polar contact	K256	K256	Preserved
Van der Waals	V248	—	Lost
Van der Waals	I250	I250	Preserved
Van der Waals	Y254	—	Lost
Hydrophobic	E173	E173	Preserved
Hydrophobic	V176	—	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

-1.26kcal/mol

Destabilising — moderate

AlphaMissense

0.872

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.754A>G

ClinVar accessionVCV000505263

Last evaluated2016/09/11 00:00

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

Structural Context

Position 252 sits in cytoplasmic domain. Neighbors: LYS253 (2.5 Å — adjacent existing lysine!), THR251 (2.5 Å), GLU249 (3.7 Å — likely salt-bridge partner with wild-type K252), VAL248 (3.7 Å).

Replacing K252 with glutamate creates two negative charges (new E252 + existing E249) where wild-type had a positive K252 + negative E249 salt bridge. The local electrostatic surface flips polarity. |ΔΔG| 1.26 reflects substantial cost. AlphaMissense 0.872 + Wolfram 1 confirm severe consequence.

Amino-acid chemistry

Lysine (K) → Glutamate (E) — positively-charged amine replaced by negatively-charged carboxylate. Complete charge reversal.

Position in the protein

N-terminal cytoplasmic domain · position 252 (pLDDT 87).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 1.26 — fold survives at meaningful cost. AlphaMissense 0.872 + Wolfram 1 confirm severe consequence.

Mechanism: charge-flip disrupting K252-E249 salt bridge + creating two-glutamate cluster. Therapeutic: site-directed at the 249-253 microregion.

Why this matters

K252E continues the charge-flip class (with E169K, E809K, E864K, K705E). Recognition-surface disruption through charge sign reversal.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the K252E 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 K252E PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A