L833Q

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

Leucine → Glutamine at position 833 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L833 — hydrogen bond to G831

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DynaMut2 mutant · L833Q

Mutant Q833 — polar contact to S835 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q687	Q687	Preserved
Hydrogen bond	—	L693	Gained
Hydrogen bond	G831	G831	Preserved
Polar contact	Y669	—	Lost
Polar contact	Q687	Q687	Preserved
Polar contact	C690	C690	Preserved
Polar contact	G831	G831	Preserved
Polar contact	S835	—	Lost
Van der Waals	C690	—	Lost
Van der Waals	—	E694	Gained
Van der Waals	G831	G831	Preserved
Van der Waals	S835	S835	Preserved
Hydrophobic	Y669	—	Lost
Hydrophobic	C690	C690	Preserved
Hydrophobic	E694	—	Lost
Hydrophobic	L829	—	Lost
Hydrophobic	F840	—	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

-1.57kcal/mol

Destabilising — moderate

AlphaMissense

0.986

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Hearing impairment

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2498T>A

ClinVar accessionVCV001064886

Last evaluated2026/03/27 00:00

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

Full Variant Card

WFS1 Wolframin — L833Q Variant Card

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

Leucine → Glutamine at position 833. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.986, DynaMut2 ΔΔG -1.57 kcal/mol (destabilising).

Identity

Field	Value
Variant	L833Q (p.Leucine833Glutamine)
DNA change	c.2498T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001064886
Amino acid change	Leucine (L) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 833	85.69 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 833 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 833 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 medium hydrophobic (leucine — branched); the mutant is polar amide (glutamine — 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	0.9861
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.57 (Destabilising)
Job ID	178092089608
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092089608

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/03/27 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	L833Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6
Hearing impairment

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|=1.57 < 2 kcal/mol (fold intact) + AlphaMissense 0.986 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|=1.57 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.986. 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
L833Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 833 with ball-and-stick + neighbors within 5Å)
L833Q_variant_card.md — this card (source of truth)
L833Q_variant_card.html — styled printable card
L833Q_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)
L833Q_wildtype_interactions.pse / L833Q_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 L833Q 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 L833Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.