R805W

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Arginine → Tryptophan at position 805 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Tryptophan at position 805 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.487 (borderline), ΔΔG +0.26 STABILISING. R→W class — aromatic replaces charge.

Interactive 3D Structure

Wild-type reference

Wild-type R805 — ionic bond to E776

Fullscreen ↗

DynaMut2 mutant · R805W

Mutant W805 — ionic bond contact to E776 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

1 lost3 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E776	—	Lost
Hydrogen bond	F775	F775	Preserved
Hydrogen bond	—	E776	Gained
Hydrogen bond	F840	F840	Preserved
Hydrogen bond	E841	E841	Preserved
Hydrogen bond	L842	L842	Preserved
Polar contact	F775	F775	Preserved
Polar contact	E776	E776	Preserved
Polar contact	F840	F840	Preserved
Polar contact	L842	L842	Preserved
Van der Waals	—	E776	Gained
Van der Waals	—	V839	Gained
Hydrophobic	E776	E776	Preserved
Hydrophobic	V839	V839	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

0.26kcal/mol

Stabilising — mild

AlphaMissense

0.487

Amb

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)

InheritanceNot specified.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0022%

cDNA changec.2413C>T

ClinVar accessionVCV001675945

Last evaluated2024/10/28 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 805 in lumenal domain. Neighbors: ALA806 (2.4 Å — A806P), LEU804 (2.5 Å — L804P!), PHE775 (3.4 Å — F775V!), PHE840 (3.7 Å).

R805 sits in the dense 804-806 cluster (with L804P, A806P) and contacts F775 (F775V). Replacing R805 with tryptophan eliminates the positive charge and creates a tryptophan-phenylalanine aromatic cluster with F775 + F840. The variant fold packs efficiently (+0.26).

AM 0.487 borderline; ClinVar Conflicting. The mechanism is loss of R805 charge from the F775-R805 ionic/cation-π contact discussed in F775V Atlas card.

Amino-acid chemistry

Arginine (R) → Tryptophan (W) — long positively-charged guanidinium replaced by bulky aromatic indole.

Position in the protein

C-terminal lumenal domain · position 805 (pLDDT 91).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG = +0.26 stabilising. AlphaMissense 0.487 borderline.

Mechanism: loss of R805 cation-π contribution to F775 contact. Therapeutic: same 775-806 microregion (with L804P, A806P, F775V).

Why this matters

R805W is the fifth variant in the dense 775-806 microregion.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R805W 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 R805W PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal