C755R

Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateSource card

Cysteine → Arginine at position 755 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type C755 — hydrogen bond to C742

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DynaMut2 mutant · C755R

Mutant R755 — hydrogen bond contact to C742 lost

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Bond changes · DynaMut2 interaction analysis

1 lost12 gained14 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	P740	Gained
Hydrogen bond	—	A741	Gained
Hydrogen bond	C742	C742	Preserved
Hydrogen bond	—	S743	Gained
Hydrogen bond	—	T747	Gained
Hydrogen bond	E751	E751	Preserved
Hydrogen bond	E752	E752	Preserved
Hydrogen bond	K758	K758	Preserved
Polar contact	P740	P740	Preserved
Polar contact	—	A741	Gained
Polar contact	C742	C742	Preserved
Polar contact	—	S743	Gained
Polar contact	—	T747	Gained
Polar contact	E751	E751	Preserved
Polar contact	E752	E752	Preserved
Polar contact	E753	E753	Preserved
Polar contact	L757	—	Lost
Polar contact	K758	K758	Preserved
Van der Waals	P740	P740	Preserved
Van der Waals	—	T747	Gained
Van der Waals	—	E751	Gained
Van der Waals	—	E752	Gained
Van der Waals	E753	E753	Preserved
Van der Waals	—	L757	Gained
Van der Waals	K758	K758	Preserved
Hydrophobic	—	P740	Gained
Hydrophobic	C742	C742	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

-1.14kcal/mol

Destabilising — moderate

AlphaMissense

0.965

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationLikely pathogenic/Likely risk allele

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00037%

cDNA changec.2263T>C

ClinVar accessionVCV000209206

Last evaluated2021/08/06 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — C755R Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Cysteine → Arginine at position 755. C-terminal ER-lumenal (calcium binding. ClinVar Likely pathogenic/Likely risk allele, AlphaMissense 0.965, DynaMut2 ΔΔG -1.14 kcal/mol (destabilising).

Identity

Field	Value
Variant	C755R (p.Cysteine755Arginine)
DNA change	c.2263T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000209206
Amino acid change	Cysteine (C) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 755	83.75 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 755 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 755 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is thiol (cysteine — disulfide-capable, free -SH); the mutant is positively charged (arginine — guanidinium, strong H-bond donor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9653
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.14 (Destabilising)
Job ID	178094553672
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094553672

Clinical Evidence

Field	Value
Classification	Likely pathogenic/Likely risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2021/08/06 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	C755R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.14 < 2 kcal/mol (fold intact) + AlphaMissense 0.965 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.14 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.965. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
C755R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 755 with ball-and-stick + neighbors within 5Å)
C755R_variant_card.md — this card (source of truth)
C755R_variant_card.html — styled printable card
C755R_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
C755R_wildtype_interactions.pse / C755R_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the C755R 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 C755R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.