H763Q

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Histidine → Glutamine at position 763 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type H763 — ionic bond to D729

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DynaMut2 mutant · H763Q

Mutant Q763 — ionic bond to D729 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost3 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	D729	—	Lost
Hydrogen bond	D729	—	Lost
Hydrogen bond	A761	A761	Preserved
Hydrogen bond	—	C765	Gained
Polar contact	D729	—	Lost
Polar contact	Y739	Y739	Preserved
Polar contact	A761	A761	Preserved
Polar contact	—	C765	Gained
Van der Waals	—	A761	Gained
Van der Waals	C765	C765	Preserved

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

0.66kcal/mol

Stabilising — mild

AlphaMissense

0.458

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.00034%

cDNA changec.2289C>A

ClinVar accessionVCV004634773

Last evaluated2025/12/04 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — H763Q Variant Card

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

Histidine → Glutamine at position 763. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.458, DynaMut2 ΔΔG +0.66 kcal/mol (stabilising).

Identity

Field	Value
Variant	H763Q (p.Histidine763Glutamine)
DNA change	c.2289C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004634773
Amino acid change	Histidine (H) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 763	83.88 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 763 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 763 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 titratable basic (histidine — imidazole); 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	0.4583
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.66 (Stabilising)
Job ID	178094702621
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094702621

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/12/04 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	H763Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.66 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.66 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.458. 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
H763Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 763 with ball-and-stick + neighbors within 5Å)
H763Q_variant_card.md — this card (source of truth)
H763Q_variant_card.html — styled printable card
H763Q_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)
H763Q_wildtype_interactions.pse / H763Q_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 H763Q 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 H763Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.