R232C

Category 4 — Stable Fold, Function DisruptedUncertain significanceCytoplasmic · predictedSource card

Arginine → Cysteine at position 232 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R232 — hydrogen bond to R228

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DynaMut2 mutant · R232C

Mutant C232 — hydrogen bond to M229 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R228	R228	Preserved
Hydrogen bond	M229	M229	Preserved
Hydrogen bond	S235	S235	Preserved
Hydrogen bond	S236	S236	Preserved
Hydrogen bond	—	L263	Gained
Hydrogen bond	N373	—	Lost
Polar contact	R228	R228	Preserved
Polar contact	M229	M229	Preserved
Polar contact	L230	L230	Preserved
Polar contact	S235	S235	Preserved
Polar contact	S236	S236	Preserved
Polar contact	L263	—	Lost
Polar contact	N373	—	Lost
Van der Waals	R228	—	Lost
Van der Waals	L230	—	Lost
Van der Waals	—	S236	Gained
Hydrophobic	L263	L263	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

0.33kcal/mol

Stabilising — mild

AlphaMissense

0.364

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00056%

cDNA changec.694C>T

ClinVar accessionVCV003650039

Last evaluated2024/09/08 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R232C Variant Card

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

Arginine → Cysteine at position 232. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.364, DynaMut2 ΔΔG +0.33 kcal/mol (stabilising).

Identity

Field	Value
Variant	R232C (p.Arginine232Cysteine)
DNA change	c.694C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003650039
Amino acid change	Arginine (R) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 232	75.56 — well-folded
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 232 sits in N-terminal cytoplasmic (intrinsically disordered). 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	0.3636
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.33 (Stabilising)
Job ID	178094720683
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094720683

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/09/08 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R232C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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|=0.33 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.33 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.364. 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
R232C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 232 with ball-and-stick + neighbors within 5Å)
R232C_variant_card.md — this card (source of truth)
R232C_variant_card.html — styled printable card
R232C_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)
R232C_wildtype_interactions.pse / R232C_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 R232C 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 R232C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.