W678G

Category 2 — Moderately DestabilizingUncertain significanceLumenal · predictedσ-1 candidateSource card

Tryptophan → Glycine 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

Fullscreen ↗

DynaMut2 mutant · W678G

Mutant G678 — hydrogen bond to G834 lost (13 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

13 lost0 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	C673	—	Lost
Hydrogen bond	G674	G674	Preserved
Hydrogen bond	G834	—	Lost
Polar contact	C673	—	Lost
Polar contact	G674	G674	Preserved
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	—	Lost
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

-3.13kcal/mol

Destabilising — large

AlphaMissense

0.964

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2032T>G

ClinVar accessionVCV000666956

Last evaluated2019/02/11 00:00

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

Full Variant Card

WFS1 Wolframin — W678G Variant Card

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

Tryptophan → Glycine at position 678. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.964, DynaMut2 ΔΔG -3.13 kcal/mol (destabilising).

Identity

Field	Value
Variant	W678G (p.Tryptophan678Glycine)
DNA change	c.2032T>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000666956
Amino acid change	Tryptophan (W) → Glycine (G)

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 small/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9636
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-3.13 (Destabilising)
Job ID	178092098041
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092098041

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2019/02/11 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	W678G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.13 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
W678G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 678 with ball-and-stick + neighbors within 5Å)
W678G_variant_card.md — this card (source of truth)
W678G_variant_card.html — styled printable card
W678G_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)
W678G_wildtype_interactions.pse / W678G_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 W678G 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 W678G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.