R522M

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Arginine → Methionine at position 522 · Cytoplasmic loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R522 — ionic bond to E394

Fullscreen ↗

DynaMut2 mutant · R522M

Mutant M522 — ionic bond to E394 lost (6 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

6 lost2 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E394	—	Lost
Hydrogen bond	E394	—	Lost
Hydrogen bond	K525	K525	Preserved
Polar contact	—	E391	Gained
Polar contact	E394	—	Lost
Polar contact	Q520	Q520	Preserved
Polar contact	F524	—	Lost
Polar contact	K525	K525	Preserved
Polar contact	Y530	—	Lost
Van der Waals	—	E391	Gained
Van der Waals	K525	—	Lost
Hydrophobic	K525	K525	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

-0.26kcal/mol

Destabilising — mild

AlphaMissense

0.800

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWFS1-related disorder; Inborn genetic diseases

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1565G>T

ClinVar accessionVCV002628550

Last evaluated2025/09/26 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — R522M Variant Card

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

Arginine → Methionine at position 522. Cytoplasmic loop 4. ClinVar Uncertain significance, AlphaMissense 0.800, DynaMut2 ΔΔG -0.26 kcal/mol (destabilising).

Identity

Field	Value
Variant	R522M (p.Arginine522Methionine)
DNA change	c.1565G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002628550
Amino acid change	Arginine (R) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 522	76.88 — well-folded
Domain	Cytoplasmic loop 4
Position context	Loop region · position 522 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 522 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); the mutant is hydrophobic sulfur (methionine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.7998
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.26 (Destabilising)
Job ID	178092148135
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092148135

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/09/26 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R522M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-related disorder
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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.26 < 2 kcal/mol (fold intact) + AlphaMissense 0.800 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|=0.26 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.800. 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
R522M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 522 with ball-and-stick + neighbors within 5Å)
R522M_variant_card.md — this card (source of truth)
R522M_variant_card.html — styled printable card
R522M_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)
R522M_wildtype_interactions.pse / R522M_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 R522M 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 R522M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.