G834S

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

Glycine → Serine at position 834 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type G834 — hydrogen bond to Y669

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DynaMut2 mutant · G834S

Mutant S834 — energy-minimized; 6 new contacts formed

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Bond changes · DynaMut2 interaction analysis

0 lost6 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y669	Y669	Preserved
Hydrogen bond	C673	C673	Preserved
Hydrogen bond	W678	W678	Preserved
Hydrogen bond	—	C690	Gained
Polar contact	Y669	Y669	Preserved
Polar contact	C673	C673	Preserved
Polar contact	W678	W678	Preserved
Polar contact	—	T686	Gained
Polar contact	—	Q687	Gained
Polar contact	—	C690	Gained
Van der Waals	—	W678	Gained
Van der Waals	—	C690	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

-1.20kcal/mol

Destabilising — moderate

AlphaMissense

0.990

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 0.00041%

cDNA changec.2500G>A

ClinVar accessionVCV000095324

Last evaluated2013/10/08 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — G834S Variant Card

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

Glycine → Serine at position 834. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.990, DynaMut2 ΔΔG -1.20 kcal/mol (destabilising).

Identity

Field	Value
Variant	G834S (p.Glycine834Serine)
DNA change	c.2500G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000095324
Amino acid change	Glycine (G) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 834	82.94 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 834 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 834 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 small/flexible (glycine — backbone flexibility, no sidechain); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9901
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.2 (Destabilising)
Job ID	178092088433
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092088433

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2013/10/08 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	G834S 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|=1.20 < 2 kcal/mol (fold intact) + AlphaMissense 0.990 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|=1.20 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.990. 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
G834S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 834 with ball-and-stick + neighbors within 5Å)
G834S_variant_card.md — this card (source of truth)
G834S_variant_card.html — styled printable card
G834S_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)
G834S_wildtype_interactions.pse / G834S_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 G834S 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 G834S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.