S835C

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

Serine → Cysteine at position 835 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S835 — hydrogen bond to R832

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DynaMut2 mutant · S835C

Mutant C835 — hydrogen bond contact to R832 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R832	R832	Preserved
Hydrogen bond	P838	P838	Preserved
Polar contact	W678	W678	Preserved
Polar contact	R832	R832	Preserved
Polar contact	L833	L833	Preserved
Polar contact	W837	W837	Preserved
Van der Waals	W678	W678	Preserved
Van der Waals	R832	R832	Preserved
Van der Waals	L833	L833	Preserved
Van der Waals	W837	—	Lost
Hydrophobic	—	R832	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

-0.32kcal/mol

Destabilising — mild

AlphaMissense

0.837

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 conditionsAutosomal dominant nonsyndromic hearing loss 6

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2503A>T

ClinVar accessionVCV003376777

Last evaluated2022/06/24 00:00

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

Full Variant Card

WFS1 Wolframin — S835C Variant Card

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

Serine → Cysteine at position 835. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.837, DynaMut2 ΔΔG -0.32 kcal/mol (destabilising).

Identity

Field	Value
Variant	S835C (p.Serine835Cysteine)
DNA change	c.2503A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003376777
Amino acid change	Serine (S) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 835	83.81 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 835 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 835 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 thiol (cysteine — disulfide-capable, free -SH). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8368
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.32 (Destabilising)
Job ID	178092113419
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092113419

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/06/24 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	S835C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6

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|=0.32 < 2 kcal/mol (fold intact) + AlphaMissense 0.837 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|=0.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.837. 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
S835C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 835 with ball-and-stick + neighbors within 5Å)
S835C_variant_card.md — this card (source of truth)
S835C_variant_card.html — styled printable card
S835C_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)
S835C_wildtype_interactions.pse / S835C_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 S835C 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 S835C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.