L445V

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Leucine → Valine at position 445 · TM4 (427-447), helical transmembrane · WFS1 (Wolframin)

Leu→Val p445 TM4 AM=0.10 ddg=+0.32 pLDDT=84. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type L445 — hydrogen bond to V441

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DynaMut2 mutant · L445V

Mutant V445 — hydrogen bond to V441 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost2 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V441	V441	Preserved
Hydrogen bond	—	T442	Gained
Polar contact	V441	V441	Preserved
Polar contact	T442	T442	Preserved
Polar contact	S443	S443	Preserved
Polar contact	—	L447	Gained
Van der Waals	V441	—	Lost
Van der Waals	S443	—	Lost
Hydrophobic	V441	—	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

0.32kcal/mol

Stabilising — mild

AlphaMissense

0.096

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0060%

cDNA changec.1333C>G

ClinVar accessionVCV000349318

Last evaluated2025/09/02 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: SER446 (2.5 Å), TYR444 (2.5 Å — partner of S443R), THR442 (3.8 Å). Near S443R cluster. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

conservative volume reduction

Position in the protein

TM4 (427-447)

Druggability Assessment

Cat 4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

Why this matters

TM4 cluster adjacent to S443R.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L445V 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 L445V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane427–447 · Helical