G728D
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 | — | R732 | Gained |
| Hydrogen bond | P724 | P724 | Preserved |
| Hydrogen bond | — | F725 | Gained |
| Hydrogen bond | M731 | M731 | Preserved |
| Hydrogen bond | R732 | R732 | Preserved |
| Polar contact | I720 | I720 | Preserved |
| Polar contact | P724 | P724 | Preserved |
| Polar contact | F725 | F725 | Preserved |
| Polar contact | M731 | M731 | Preserved |
| Polar contact | R732 | R732 | Preserved |
| Van der Waals | I720 | — | Lost |
| Van der Waals | — | F725 | Gained |
| Van der Waals | — | R732 | Gained |
| Hydrophobic | — | I720 | Gained |
| Hydrophobic | — | L723 | 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Full Variant Card
WFS1 Wolframin — G728D Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Glycine → Aspartic acid at position 728. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.865, DynaMut2 ΔΔG -1.65 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | G728D (p.Glycine728Aspartic acid) |
| DNA change | c.2183G>A |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV000591295 |
| Amino acid change | Glycine (G) → Aspartic acid (D) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 728 | 86.00 — well-folded |
| Domain | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| Position context | C-terminal lumenal domain · position 728 projects into the ER lumen |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 728 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/flexible (glycine — backbone flexibility, no sidechain); 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 | 0.8653 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -1.65 (Destabilising) |
| Job ID | 178092110699 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092110699 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance/Uncertain risk allele |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2022/03/29 00:00 |
| Inheritance | Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6). |
| WFS1 variant landscape | G728D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |
- Wolfram-like syndrome
- Cataract 41
- Autosomal dominant nonsyndromic hearing loss 6
- Type 2 diabetes mellitus
- 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|=1.65 < 2 kcal/mol (fold intact) + AlphaMissense 0.865 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|=1.65 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.865. 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 structureG728D_molstar_viewer.html— interactive 3D viewer (auto-highlights position 728 with ball-and-stick + neighbors within 5Å)G728D_variant_card.md— this card (source of truth)G728D_variant_card.html— styled printable cardG728D_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)G728D_wildtype_interactions.pse/G728D_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 G728D 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.