V219A
Category 4 — Stable Fold, Function DisruptedUncertain significanceCytoplasmic · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Polar contact | G217 | G217 | Preserved |
| Polar contact | K221 | K221 | Preserved |
| Hydrophobic | L223 | — | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — V219A Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Valine → Alanine at position 219. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.377, DynaMut2 ΔΔG -0.42 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | V219A (p.Valine219Alanine) |
| DNA change | c.656T>C |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV001411691 |
| Amino acid change | Valine (V) → Alanine (A) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 219 | 53.28 — confident |
| Domain | N-terminal cytoplasmic (intrinsically disordered) |
| Position context | N-terminal cytoplasmic (intrinsically disordered) |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 219 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small hydrophobic (valine — branched); the mutant is small/hydrophobic (alanine — methyl sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.3766 |
| am_class | ambiguous |
| Interpretation | Likely benign (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.42 (Destabilising) |
| Job ID | 178094704517 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094704517 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/08/19 00:00 |
| Inheritance | Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6). |
| WFS1 variant landscape | V219A 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-like syndrome
- Cataract 41
- 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 4 — Stable Fold, Function Disrupted
<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.42 negligible. Likely site-specific functional disruption — docking strategy.
Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.42 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.377. 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 structureV219A_molstar_viewer.html— interactive 3D viewer (auto-highlights position 219 with ball-and-stick + neighbors within 5Å)V219A_variant_card.md— this card (source of truth)V219A_variant_card.html— styled printable cardV219A_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)V219A_wildtype_interactions.pse/V219A_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 V219A 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.