G398R

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Glycine → Arginine at position 398 · Cytoplasmic loop 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type G398 — hydrogen bond to E394

Fullscreen ↗

DynaMut2 mutant · G398R

Mutant R398 — van der waals contact to L402 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

1 lost5 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E394	E394	Preserved
Hydrogen bond	V395	V395	Preserved
Hydrogen bond	H401	H401	Preserved
Hydrogen bond	L402	L402	Preserved
Polar contact	E394	E394	Preserved
Polar contact	V395	V395	Preserved
Polar contact	—	N400	Gained
Polar contact	H401	H401	Preserved
Polar contact	L402	L402	Preserved
Carbonyl	—	H401	Gained
Van der Waals	V395	V395	Preserved
Van der Waals	—	N400	Gained
Van der Waals	—	H401	Gained
Van der Waals	L402	—	Lost
Hydrophobic	—	Y528	Gained

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

-0.22kcal/mol

Destabilising — mild

AlphaMissense

0.889

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 0.00012%

cDNA changec.1192G>C

ClinVar accessionVCV000215411

Last evaluated2014/09/18 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — G398R Variant Card

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

Glycine → Arginine at position 398. Cytoplasmic loop 2. ClinVar Uncertain significance, AlphaMissense 0.889, DynaMut2 ΔΔG -0.22 kcal/mol (destabilising).

Identity

Field	Value
Variant	G398R (p.Glycine398Arginine)
DNA change	c.1192G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000215411
Amino acid change	Glycine (G) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 398	78.38 — well-folded
Domain	Cytoplasmic loop 2
Position context	Loop region · position 398 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 398 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 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	0.8886
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.22 (Destabilising)
Job ID	178092108498
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092108498

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2014/09/18 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	G398R 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|=0.22 < 2 kcal/mol (fold intact) + AlphaMissense 0.889 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|=0.22 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.889. 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
G398R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 398 with ball-and-stick + neighbors within 5Å)
G398R_variant_card.md — this card (source of truth)
G398R_variant_card.html — styled printable card
G398R_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)
G398R_wildtype_interactions.pse / G398R_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 G398R 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 G398R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.