D379N

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Aspartate → Asparagine at position 379 · Connecting loop · WFS1 (Wolframin)

Asp→Asn p379 loop AM=0.10 ddg=-0.53 pLDDT=84. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type D379 — hydrogen bond to R375

Fullscreen ↗

DynaMut2 mutant · D379N

Mutant N379 — polar contact contact to R375 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

1 lost1 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R375	R375	Preserved
Hydrogen bond	L382	L382	Preserved
Hydrogen bond	R383	R383	Preserved
Polar contact	R375	R375	Preserved
Polar contact	L377	L377	Preserved
Polar contact	—	L382	Gained
Van der Waals	R375	—	Lost
Van der Waals	L377	L377	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

-0.53kcal/mol

Destabilising — mild

AlphaMissense

0.098

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 0.0023%

cDNA changec.1135G>A

ClinVar accessionVCV000215355

Last evaluated2025/11/15 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: LEU380 (2.5 Å), THR378 (2.5 Å), ARG375 (3.7 Å — likely salt-bridge partner). Loop polar network disruption. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

charge loss, H-bond preserved

Position in the protein

Connecting loop

Druggability Assessment

Cat 3/4 — 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

Loop charge-network disruption.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D379N 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 D379N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin