S826N

Category 3/4 — Most DruggableLikely risk alleleLumenal · predictedσ-1 candidateSource card

Serine → Asparagine at position 826 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S826 — hydrogen bond to A844

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DynaMut2 mutant · S826N

Mutant N826 — hydrogen bond to K843 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost5 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R697	—	Lost
Hydrogen bond	V698	V698	Preserved
Hydrogen bond	—	T699	Gained
Hydrogen bond	K843	K843	Preserved
Hydrogen bond	A844	A844	Preserved
Polar contact	V698	V698	Preserved
Polar contact	—	T699	Gained
Polar contact	K843	K843	Preserved
Polar contact	A844	A844	Preserved
Van der Waals	—	T699	Gained
Van der Waals	A844	—	Lost
Hydrophobic	—	T699	Gained
Hydrophobic	—	A844	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

-0.46kcal/mol

Destabilising — mild

AlphaMissense

0.960

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationLikely risk allele

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2477G>A

ClinVar accessionVCV001048084

Last evaluated1/01/01 00:00

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

Full Variant Card

WFS1 Wolframin — S826N Variant Card

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

Serine → Asparagine at position 826. C-terminal ER-lumenal (calcium binding. ClinVar Likely risk allele, AlphaMissense 0.960, DynaMut2 ΔΔG -0.46 kcal/mol (destabilising).

Identity

Field	Value
Variant	S826N (p.Serine826Asparagine)
DNA change	c.2477G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001048084
Amino acid change	Serine (S) → Asparagine (N)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 826	88.75 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 826 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 826 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 polar (serine — hydroxyl); the mutant is polar amide (asparagine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9597
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.46 (Destabilising)
Job ID	178094554174
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094554174

Clinical Evidence

Field	Value
Classification	Likely risk allele
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	S826N 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.46 < 2 kcal/mol (fold intact) + AlphaMissense 0.960 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|=0.46 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.960. 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
S826N_molstar_viewer.html — interactive 3D viewer (auto-highlights position 826 with ball-and-stick + neighbors within 5Å)
S826N_variant_card.md — this card (source of truth)
S826N_variant_card.html — styled printable card
S826N_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)
S826N_wildtype_interactions.pse / S826N_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 S826N 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 S826N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.