D305Y
Category 4 — Stable Fold, Function DisruptedUncertain significanceCytoplasmic · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R309 | — | Lost |
| Hydrogen bond | E301 | E301 | Preserved |
| Hydrogen bond | S308 | S308 | Preserved |
| Hydrogen bond | R309 | R309 | Preserved |
| Polar contact | E301 | E301 | Preserved |
| Polar contact | Y302 | Y302 | Preserved |
| Polar contact | S308 | S308 | Preserved |
| Polar contact | R309 | R309 | 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 at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — D305Y Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Aspartic acid → Tyrosine at position 305. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.489, DynaMut2 ΔΔG +0.43 kcal/mol (stabilising).
Identity
| Field | Value |
|---|---|
| Variant | D305Y (p.Aspartic acid305Tyrosine) |
| DNA change | c.913G>T |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV003364921 |
| Amino acid change | Aspartic acid (D) → Tyrosine (Y) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 305 | 67.12 — 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 305 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is negatively charged (aspartate — carboxylate); the mutant is aromatic with hydroxyl (tyrosine — 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 | 0.4889 |
| am_class | ambiguous |
| Interpretation | Likely benign (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | 0.43 (Stabilising) |
| Job ID | 178094719601 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094719601 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/11/29 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | D305Y 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 4 — Stable Fold, Function Disrupted
<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.43 negligible. Likely site-specific functional disruption — docking strategy.
Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.43 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.489. 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 structureD305Y_molstar_viewer.html— interactive 3D viewer (auto-highlights position 305 with ball-and-stick + neighbors within 5Å)D305Y_variant_card.md— this card (source of truth)D305Y_variant_card.html— styled printable cardD305Y_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)D305Y_wildtype_interactions.pse/D305Y_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 D305Y 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.