H766D
Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E737 | — | Lost |
| Hydrogen bond | E737 | E737 | Preserved |
| Hydrogen bond | Y739 | — | Lost |
| Hydrogen bond | K768 | K768 | Preserved |
| Polar contact | G736 | — | Lost |
| Polar contact | E737 | E737 | Preserved |
| Polar contact | — | Y739 | Gained |
| Polar contact | — | K768 | Gained |
| Aromatic / π | Y739 | — | Lost |
| Carbonyl | G736 | — | Lost |
| Van der Waals | G736 | — | Lost |
| Van der Waals | Y739 | Y739 | Preserved |
| Van der Waals | — | K768 | Gained |
| Hydrophobic | Y739 | Y739 | Preserved |
| Hydrophobic | K768 | K768 | 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Full Variant Card
WFS1 Wolframin — H766D Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Histidine → Aspartic acid at position 766. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.817, DynaMut2 ΔΔG -0.29 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | H766D (p.Histidine766Aspartic acid) |
| DNA change | c.2296C>G |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV000546958 |
| Amino acid change | Histidine (H) → Aspartic acid (D) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 766 | 89.25 — well-folded |
| Domain | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| Position context | C-terminal lumenal domain · position 766 projects into the ER lumen |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 766 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 negatively charged (aspartate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.8173 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.29 (Destabilising) |
| Job ID | 178092114748 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092114748 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, single submitter |
| Last evaluated | 2018/03/01 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | H766D 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|=0.29 < 2 kcal/mol (fold intact) + AlphaMissense 0.817 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|=0.29 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.817. 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 structureH766D_molstar_viewer.html— interactive 3D viewer (auto-highlights position 766 with ball-and-stick + neighbors within 5Å)H766D_variant_card.md— this card (source of truth)H766D_variant_card.html— styled printable cardH766D_dynamut2_summary.html— clean offline DynaMut2 result carddynamut2_result.json— structured result datadynamut2_result_page.html— local snapshot of the Biosig result page (asset URLs absolutized)H766D_wildtype_interactions.pse/H766D_mutant_interactions.pse— PyMOL sessions
Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.
Feed this card to Wolfram Intelligence
Download the H766D 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.