V412L

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Valine → Leucine at position 412 · TM3 (402-422), helical transmembrane · WFS1 (Wolframin)

Valine → Leucine at position 412 inside TM3. ClinVar Conflicting. AlphaMissense 0.663, ΔΔG -0.47. Same position as V412A. Conservative branched-aliphatic swap.

Interactive 3D Structure

Wild-type reference

Wild-type V412 — hydrogen bond to F408

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DynaMut2 mutant · V412L

Mutant L412 — hydrogen bond contact to M357 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained17 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M357	M357	Preserved
Hydrogen bond	F408	F408	Preserved
Hydrogen bond	L409	L409	Preserved
Hydrogen bond	V415	V415	Preserved
Hydrogen bond	I416	I416	Preserved
Polar contact	M357	M357	Preserved
Polar contact	F408	F408	Preserved
Polar contact	L409	L409	Preserved
Polar contact	F414	F414	Preserved
Polar contact	V415	V415	Preserved
Polar contact	I416	I416	Preserved
Van der Waals	—	M357	Gained
Van der Waals	F408	F408	Preserved
Van der Waals	F414	F414	Preserved
Van der Waals	I416	I416	Preserved
Hydrophobic	M357	M357	Preserved
Hydrophobic	F408	F408	Preserved
Hydrophobic	I416	—	Lost
Hydrophobic	M539	M539	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

-0.47kcal/mol

Destabilising — mild

AlphaMissense

0.663

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 conditionsWFS1-Related Spectrum Disorders

InheritanceWFS1 spectrum.

Population frequency (gnomAD v4)Low frequency · AF 0.015%

cDNA changec.1234G>C

ClinVar accessionVCV000143131

Last evaluated2024/09/23 00:00

Observed in the general population.

Structural Context

Position 412 in TM3. Neighbors: PHE413 (2.5 Å), SER411 (2.5 Å), LEU409 (3.8 Å), PHE408 (3.9 Å — TM3-TM7 interface position).

Replacing V412 with leucine is the most conservative substitution at this position. Yet ΔΔG -0.47 + AM 0.663 + WFS1 spectrum confirm pathogenicity. Mechanism is volume mismatch with surrounding F413, S411 environment and perturbation of the F408 TM3-TM7 contact.

Amino-acid chemistry

Valine (V) → Leucine (L) — branched aliphatic to branched aliphatic. Modest volume increase.

Position in the protein

TM3 (residues 402–422) · position 412 (pLDDT 94).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.47. AlphaMissense 0.663 confirms pathogenicity.

Mechanism: conservative volume mismatch in TM3 + F408 interface perturbation. Therapeutic: TM3-TM7 interface.

Why this matters

V412L + V412A at same position — both pathogenic despite extremely conservative chemistry. Position 412 in TM3 is structurally inflexible.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V412L 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 V412L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane402–422 · Helical