M518K

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Methionine → Lysine at position 518 · Connecting loop · WFS1 (Wolframin)

Methionine → Lysine at position 518 in a connecting loop. ClinVar Conflicting including optic neuropathy. AlphaMissense 0.925, ΔΔG -0.64 (destabilising). Same position as M518I (Atlas card).

Interactive 3D Structure

Wild-type reference

Wild-type M518 — hydrogen bond to L521

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DynaMut2 mutant · M518K

Mutant K518 — hydrogen bond to L521 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost4 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L514	L514	Preserved
Hydrogen bond	F515	F515	Preserved
Hydrogen bond	L521	L521	Preserved
Hydrogen bond	—	G526	Gained
Polar contact	L514	L514	Preserved
Polar contact	F515	F515	Preserved
Polar contact	L521	L521	Preserved
Van der Waals	—	A458	Gained
Van der Waals	—	L514	Gained
Van der Waals	—	L521	Gained
Hydrophobic	Y454	—	Lost
Hydrophobic	T455	T455	Preserved
Hydrophobic	A458	—	Lost
Hydrophobic	L514	—	Lost
Hydrophobic	F515	—	Lost
Hydrophobic	Y534	Y534	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

-0.64kcal/mol

Destabilising — mild

AlphaMissense

0.925

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 conditionsOptic neuropathy

InheritanceOptic neuropathy documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0013%

cDNA changec.1553T>A

ClinVar accessionVCV001320487

Last evaluated2025/08/01 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 518 same neighbors as M518I: ALA519 (2.5 Å), ARG517 (2.5 Å — adjacent existing arginine), PHE515 (3.7 Å), LEU514 (3.8 Å), LEU521 (3.9 Å).

M518K is the second substitution at position 518. Unlike M518I (conservative hydrophobic-to-hydrophobic), M518K introduces a charged residue. The new K518 amine adjacent to existing R517 creates a two-basic cluster where wild-type had M518's sulfur chemistry.

The |ΔΔG| of 0.64 is larger than M518I's 0.29 — the charge introduction has greater structural cost than conservative volume change. AlphaMissense 0.925 + optic neuropathy confirm severe consequence.

Amino-acid chemistry

Methionine (M) → Lysine (K) — flexible sulfur-containing hydrophobic replaced by long positively-charged amine. Charge introduction into a hydrophobic loop position.

Position in the protein

Connecting loop · position 518 (pLDDT 84). Same position as M518I.

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.64 — fold survives. AlphaMissense 0.925 + optic neuropathy confirm severe consequence.

Mechanism: charge introduction into the M518 hydrophobic environment, creating a two-basic cluster with R517. Therapeutic: same M518 microregion as M518I.

Why this matters

M518K + M518I at same position — both pathogenic but through different mechanisms (charge introduction vs lost methionine chemistry).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M518K 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 M518K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin