A433T
Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | C429 | C429 | Preserved |
| Hydrogen bond | — | S430 | Gained |
| Hydrogen bond | T436 | T436 | Preserved |
| Hydrogen bond | G437 | G437 | Preserved |
| Hydrogen bond | — | I547 | Gained |
| Polar contact | C429 | C429 | Preserved |
| Polar contact | E431 | E431 | Preserved |
| Polar contact | T436 | T436 | Preserved |
| Polar contact | G437 | G437 | Preserved |
| Polar contact | — | I547 | Gained |
| Polar contact | — | L548 | Gained |
| Van der Waals | C429 | — | Lost |
| Van der Waals | E431 | E431 | Preserved |
| Van der Waals | — | I435 | Gained |
| Van der Waals | T436 | T436 | Preserved |
| Van der Waals | — | L548 | Gained |
| Hydrophobic | I547 | — | Lost |
| Hydrophobic | — | L548 | Gained |
| Hydrophobic | L556 | L556 | 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
Observed in the general population.
Full Variant Card
WFS1 Wolframin — A433T Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Alanine → Threonine at position 433. Transmembrane helix 5. ClinVar Uncertain significance, AlphaMissense 0.342, DynaMut2 ΔΔG -1.81 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | A433T (p.Alanine433Threonine) |
| DNA change | c.1297G>A |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV000166587 |
| Amino acid change | Alanine (A) → Threonine (T) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 433 | 91.31 — well-folded |
| Domain | Transmembrane helix 5 |
| Position context | Inside Transmembrane helix 5 · position 433 is bilayer-embedded |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 433 sits in a transmembrane helix (Transmembrane helix 5). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.3415 |
| am_class | ambiguous |
| Interpretation | Likely benign (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -1.81 (Destabilising) |
| Job ID | 178094708212 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094708212 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/03/05 00:00 |
| Inheritance | Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6). |
| WFS1 variant landscape | A433T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |
- Inborn genetic diseases
- Autosomal dominant nonsyndromic hearing loss 6
- Type 2 diabetes mellitus
- Wolfram syndrome 1
- Cataract 41
- Wolfram-like syndrome
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|=1.81 negligible. Likely site-specific functional disruption — docking strategy.
Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.342. 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 structureA433T_molstar_viewer.html— interactive 3D viewer (auto-highlights position 433 with ball-and-stick + neighbors within 5Å)A433T_variant_card.md— this card (source of truth)A433T_variant_card.html— styled printable cardA433T_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)A433T_wildtype_interactions.pse/A433T_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 A433T 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.