W678R

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Tryptophan → Arginine at position 678 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type W678 — hydrogen bond to G834

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DynaMut2 mutant · W678R

Mutant R678 — hydrogen bond to G834 lost (12 contacts lost)

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Bond changes · DynaMut2 interaction analysis

12 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	C673	—	Lost
Hydrogen bond	G674	G674	Preserved
Hydrogen bond	—	P675	Gained
Hydrogen bond	G834	—	Lost
Polar contact	C673	—	Lost
Polar contact	G674	G674	Preserved
Polar contact	—	P675	Gained
Polar contact	R676	R676	Preserved
Polar contact	T681	T681	Preserved
Polar contact	G834	—	Lost
Polar contact	S835	—	Lost
Carbonyl	T681	T681	Preserved
Van der Waals	C673	—	Lost
Van der Waals	P675	—	Lost
Van der Waals	R676	R676	Preserved
Van der Waals	T681	—	Lost
Van der Waals	M683	—	Lost
Van der Waals	S835	—	Lost
Hydrophobic	P675	—	Lost
Hydrophobic	M683	M683	Preserved
Hydrophobic	K836	—	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

-0.10kcal/mol

Destabilising — mild

AlphaMissense

0.997

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)Absent from gnomAD v4

cDNA changec.2032T>A

ClinVar accessionVCV002581841

Last evaluated2023/03/30 00:00

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

Full Variant Card

WFS1 Wolframin — W678R Variant Card

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

Tryptophan → Arginine at position 678. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.997, DynaMut2 ΔΔG -0.10 kcal/mol (destabilising).

Identity

Field	Value
Variant	W678R (p.Tryptophan678Arginine)
DNA change	c.2032T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002581841
Amino acid change	Tryptophan (W) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 678	82.62 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 678 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 678 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is bulky aromatic (tryptophan — indole ring); 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	0.9973
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.1 (Destabilising)
Job ID	178090202318
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178090202318

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/03/30 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	W678R 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|=0.10 < 2 kcal/mol (fold intact) + AlphaMissense 0.997 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|=0.10 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.997. 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
W678R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 678 with ball-and-stick + neighbors within 5Å)
W678R_variant_card.md — this card (source of truth)
W678R_variant_card.html — styled printable card
W678R_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)
W678R_wildtype_interactions.pse / W678R_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 W678R 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 W678R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.