C765R

Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorial

Cysteine → Arginine at position 765 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Cysteine → Arginine at position 765 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.991 (near-maximum), DynaMut2 ΔΔG -1.06 kcal/mol (destabilising). The C765 partner residue of the C733 inferred disulfide.

Interactive 3D Structure

Wild-type reference

Wild-type C765 — hydrogen bond to A738

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DynaMut2 mutant · C765R

Mutant R765 — hydrogen bond to A738 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	C733	Gained
Hydrogen bond	A738	—	Lost
Polar contact	C733	C733	Preserved
Polar contact	E737	E737	Preserved
Carbonyl	E737	E737	Preserved
Van der Waals	E737	E737	Preserved
Van der Waals	—	A738	Gained
Van der Waals	H763	H763	Preserved
Hydrophobic	R732	—	Lost
Hydrophobic	C733	C733	Preserved
Hydrophobic	—	A738	Gained

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

-1.06kcal/mol

Destabilising — moderate

AlphaMissense

0.991

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 conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1 documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.2293T>C

ClinVar accessionVCV000166604

Last evaluated2014/11/17 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 765 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C765 within 5 Å of HIS766 (2.4 Å — partner of D771H Atlas card region), PRO764 (2.5 Å), GLU737 (3.2 Å — same E737 as G736R/G736S neighbor), ALA738 (4.0 Å), and TYR739 (4.2 Å).

C765 was the partner residue identified in the C733G Atlas card (3.5 Å distance — possible disulfide). C765R replaces the cysteine at the OTHER end of this potential disulfide. The combination of C733G (cysteine removed) + C765R (cysteine replaced by arginine) at the inferred disulfide pair confirms both cysteines are pathogenic when mutated.

The |ΔΔG| of 1.06 reflects substantial fold cost. AlphaMissense's 0.991 (near-maximum) confirms severe functional consequence.

Amino-acid chemistry

Cysteine (C) → Arginine (R) — thiol-bearing residue replaced by large positively-charged guanidinium. Loss of disulfide potential plus charge introduction.

Position in the protein

C-terminal lumenal domain · position 765 in the ER lumen (pLDDT 89).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 1.06 — fold survives. AlphaMissense 0.991 confirms severe functional consequence.

Mechanism is loss of the inferred C733-C765 disulfide bond plus charge introduction. Therapeutic strategy: site-directed at the C733-C765 microregion (same target as C733G).

Why this matters

C765R + C733G are the two pathogenic variants at opposite ends of the inferred C733-C765 disulfide. Two convergent variant targets at the same disulfide pair.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the C765R 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 C765R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal