L382P

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Leucine → Proline at position 382 · Connecting loop · WFS1 (Wolframin)

Leucine → Proline at position 382 in a connecting loop. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.922, ΔΔG -0.40 (mild destabilising). Proline-introduction in a loop region.

Interactive 3D Structure

Wild-type reference

Wild-type L382 — hydrogen bond to T378

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DynaMut2 mutant · L382P

Mutant P382 — hydrogen bond to D379 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost3 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T378	T378	Preserved
Hydrogen bond	D379	—	Lost
Hydrogen bond	E385	E385	Preserved
Polar contact	T378	T378	Preserved
Polar contact	—	D379	Gained
Polar contact	—	F384	Gained
Polar contact	—	E385	Gained
Polar contact	P386	P386	Preserved
Carbonyl	E385	E385	Preserved
Van der Waals	L380	—	Lost
Van der Waals	F384	—	Lost
Hydrophobic	L388	—	Lost
Hydrophobic	V390	—	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

-0.40kcal/mol

Destabilising — mild

AlphaMissense

0.922

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-like syndrome

InheritanceWolfram-like syndrome documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00037%

cDNA changec.1145T>C

ClinVar accessionVCV001699545

Last evaluated2024/10/17 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 382 sits in a connecting loop. Neighbors: ARG383 (2.5 Å — partner of R383H — not yet in Atlas), LEU381 (2.5 Å), GLU385 (3.6 Å — partner of E385K), THR378 (3.8 Å).

Replacing L382 with proline introduces a backbone kink in the loop. The R383 partner residue (with E385 forming a likely salt-bridge or H-bond network) experiences perturbed geometry. The |ΔΔG| of 0.40 reflects modest fold cost; AlphaMissense 0.922 + Wolfram-like confirm severe consequence.

Amino-acid chemistry

Leucine (L) → Proline (P) — branched aliphatic hydrophobic replaced by rigid helix-breaking residue.

Position in the protein

Connecting loop · position 382 (pLDDT 85).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.40 — fold survives. AlphaMissense 0.922 confirms severe consequence.

Mechanism: proline-induced backbone kink in the R383-E385 microregion. Therapeutic: same loop region (E385K adjacent).

Why this matters

L382P + E385K at adjacent positions — multi-variant target cluster in the 382-385 loop.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L382P 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 L382P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin