R228C

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

Arginine → Cysteine at position 228 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R228 — hydrogen bond to Q224

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DynaMut2 mutant · R228C

Mutant C228 — hydrogen bond contact to K225 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q224	Q224	Preserved
Hydrogen bond	K225	K225	Preserved
Hydrogen bond	E231	E231	Preserved
Hydrogen bond	R232	R232	Preserved
Polar contact	Q224	Q224	Preserved
Polar contact	K225	K225	Preserved
Polar contact	—	E231	Gained
Polar contact	R232	R232	Preserved
Van der Waals	Q224	—	Lost
Van der Waals	R232	R232	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

0.27kcal/mol

Stabilising — mild

AlphaMissense

0.353

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Common · AF 6.84%

cDNA changec.682C>T

ClinVar accessionVCV003250140

Last evaluated2025/04/12 00:00

Population frequency too high for a penetrant Wolfram allele — stand-alone benign evidence (ACMG BA1).

Full Variant Card

WFS1 Wolframin — R228C Variant Card

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

Arginine → Cysteine at position 228. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.353, DynaMut2 ΔΔG +0.27 kcal/mol (stabilising).

Identity

Field	Value
Variant	R228C (p.Arginine228Cysteine)
DNA change	c.682C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003250140
Amino acid change	Arginine (R) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 228	76.00 — 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 228 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	0.3530
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.27 (Stabilising)
Job ID	178094704238
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094704238

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/04/12 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R228C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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|=0.27 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.27 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.353. 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
R228C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 228 with ball-and-stick + neighbors within 5Å)
R228C_variant_card.md — this card (source of truth)
R228C_variant_card.html — styled printable card
R228C_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)
R228C_wildtype_interactions.pse / R228C_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 R228C 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 R228C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.