R587W

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Arginine → Tryptophan at position 587 · Connecting loop · WFS1 (Wolframin)

Arg→Trp p587 loop AM=0.10 ddg=-0.42 pLDDT=77. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type R587 — hydrogen bond to L583

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DynaMut2 mutant · R587W

Mutant W587 — polar contact contact to T590 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L583	L583	Preserved
Hydrogen bond	T590	T590	Preserved
Hydrogen bond	S591	S591	Preserved
Polar contact	L583	L583	Preserved
Polar contact	Q584	Q584	Preserved
Polar contact	T590	T590	Preserved
Polar contact	S591	S591	Preserved
Van der Waals	S591	—	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

-0.42kcal/mol

Destabilising — mild

AlphaMissense

0.100

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 0.0087%

cDNA changec.1759C>T

ClinVar accessionVCV001328081

Last evaluated2026/02/04 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: TRP588 (2.4 Å — adjacent existing W!), ALA586 (2.5 Å), THR590 (3.5 Å). Tandem W588-W587 aromatic cluster created. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

charge loss + aromatic addition

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

Tandem-aromatic creation in loop.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R587W 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 R587W PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin