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
- pLDDT 67.12 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Uncertain significance, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,984 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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 | Job 178094719601 · retrieved 2026-06-08 — result self-hosted by RareResearch.AI (Biosig no longer serves this page) |
Clinical Evidence
Inheritance and scope
Uncertain significance — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Uncertain significance, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
| 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.