G98R

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Glycine → Arginine at position 98 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type G98 — hydrogen bond to R94

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DynaMut2 mutant · G98R

Mutant R98 — van der waals contact to P100 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R94	R94	Preserved
Hydrogen bond	A95	A95	Preserved
Hydrogen bond	Q136	Q136	Preserved
Polar contact	R94	R94	Preserved
Polar contact	A95	A95	Preserved
Polar contact	K96	K96	Preserved
Polar contact	P100	P100	Preserved
Polar contact	Q136	Q136	Preserved
Van der Waals	P100	—	Lost

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

-0.85kcal/mol

Destabilising — mild

AlphaMissense

0.776

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.0012%

cDNA changec.292G>A

ClinVar accessionVCV003695493

Last evaluated2025/10/14 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — G98R Variant Card

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

Glycine → Arginine at position 98. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.776, DynaMut2 ΔΔG -0.85 kcal/mol (destabilising).

Identity

Field	Value
Variant	G98R (p.Glycine98Arginine)
DNA change	c.292G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003695493
Amino acid change	Glycine (G) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 98	83.81 — 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 98 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small/flexible (glycine — backbone flexibility, no sidechain); 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	0.7761
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.85 (Destabilising)
Job ID	178092118679
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092118679

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/10/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	G98R 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.85 < 2 kcal/mol (fold intact) + AlphaMissense 0.776 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|=0.85 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.776. 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
G98R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 98 with ball-and-stick + neighbors within 5Å)
G98R_variant_card.md — this card (source of truth)
G98R_variant_card.html — styled printable card
G98R_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)
G98R_wildtype_interactions.pse / G98R_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 G98R 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 G98R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.