R756C

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Arginine → Cysteine at position 756 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R756 — ionic bond to E752

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DynaMut2 mutant · R756C

Mutant C756 — ionic bond contact to E752 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E752	—	Lost
Hydrogen bond	E752	E752	Preserved
Hydrogen bond	E753	E753	Preserved
Hydrogen bond	L759	L759	Preserved
Polar contact	E752	E752	Preserved
Polar contact	E753	E753	Preserved
Polar contact	K758	K758	Preserved
Polar contact	L759	L759	Preserved
Van der Waals	—	E752	Gained
Van der Waals	—	L754	Gained
Van der Waals	K758	K758	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

0.32kcal/mol

Stabilising — mild

AlphaMissense

0.385

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram-like syndrome; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Cataract 41

Population frequency (gnomAD v4)Low frequency · AF 0.018%

cDNA changec.2266C>T

ClinVar accessionVCV001695517

Last evaluated2026/01/21 00:00

Observed in the general population.

Full Variant Card

WFS1 Wolframin — R756C Variant Card

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

Arginine → Cysteine at position 756. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.385, DynaMut2 ΔΔG +0.32 kcal/mol (stabilising).

Identity

Field	Value
Variant	R756C (p.Arginine756Cysteine)
DNA change	c.2266C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001695517
Amino acid change	Arginine (R) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 756	83.44 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 756 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 756 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 positively charged (arginine — guanidinium, strong H-bond donor); the mutant is thiol (cysteine — disulfide-capable, free -SH). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3854
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.32 (Stabilising)
Job ID	178094703908
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094703908

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/01/21 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	R756C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram-like syndrome
Wolfram syndrome 1
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
Cataract 41

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.32 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.385. 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
R756C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 756 with ball-and-stick + neighbors within 5Å)
R756C_variant_card.md — this card (source of truth)
R756C_variant_card.html — styled printable card
R756C_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)
R756C_wildtype_interactions.pse / R756C_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 R756C 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 R756C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.