A48V
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedSource cardInteractive 3D Structure
Computational Predictions
- pLDDT 25.08 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 Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "Inborn genetic diseases", "not specified", "not provided". 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0010% (12 of 1,160,602 alleles), in line with the global figure.
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) | 0.0010% | 12 / 1,160,602 | 0 | ~1 in 48360 |
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 — A48V Variant Card
Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo
Prepared: May 26, 2026 · Schema target: Category 5 — IDR EXCLUSION
Identity
| Field | Value |
|---|---|
| Variant | A48V |
| DNA change | c.143C>T |
| Gene | WFS1 |
| Protein | Wolframin (890 aa) |
| UniProt ID | O76024 |
| ClinVar accession | VCV000045435 |
| Amino acid change | A → V at position 48 |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 48 | 25.08 |
| Domain | N-terminal intrinsically disordered region (1-86) |
| UniProt features at this position |
- Chain: 1-890 Wolframin
- Region: 1-321 Interaction with ATP6V1A
- Region: 1-86 Disordered
Position 48, pLDDT 25.08. This residue belongs to wolframin's disordered N-terminal region (residues 1–86), annotated by UniProt as the ATP6V1A interaction region but lacking defined secondary structure. AlphaFold's confidence is below the IDR threshold of 50 — meaning the model is essentially a guess about local geometry.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.0750 |
| am_class | LBen |
| Interpretation | Likely benign per AlphaMissense |
DynaMut2
| Field | Value |
|---|---|
| Job ID | 177985960542 |
| ΔΔG (kcal/mol) | -0.75 kcal/mol (Destabilising) |
| Result URL | Job 177985960542 · retrieved 2026-05-27 — result self-hosted by RareResearch.AI (Biosig no longer serves this page) |
Clinical Evidence
Inheritance and scope
Conflicting classifications of pathogenicity — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "Inborn genetic diseases", "not specified", "not provided". 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 |
|---|---|
| ClinVar classification | Conflicting classifications of pathogenicity |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/20 00:00 |
| Associated conditions | Inborn genetic diseases; not specified; not provided; Wolfram syndrome 1 |
Computational vs Clinical Tension
AlphaMissense 0.075 (LBen — Likely Benign). ClinVar shows Conflicting classifications of pathogenicity — submitting labs cannot agree. Some call it Wolfram syndrome 1; others call it benign. The Atlas resolves this tension by refusing to take a structural position: in an IDR, structure-based predictions are unreliable, and the variant must be triaged to wet-lab functional validation (cell-based assays, family segregation, RNA effects).
Phenotype focus
Reported in Wolfram syndrome 1 by some submitters; benign by others — clinical signal unresolved
Carrier story
A48V is a litmus test for the Atlas's intellectual honesty. It sits at position 48 in the N-terminal intrinsically disordered region, pLDDT 25.08 — deep in the floppy zone where no static model can support reliable structure-function inference.
Mechanism hypothesis
If DynaMut2 returns any specific ΔΔG, that value is not trustworthy for a low-pLDDT residue — DynaMut2 assumes a meaningful starting structure. The correct schema output for A48V is Category 5 — exclude from druggability prediction; flag for experimental validation only. This is the Atlas saying 'I don't know — and here's why.'
Files in this folder
AF-O76024-F1-model_v6.pdb— AlphaFold structureA48V_molstar_viewer.html— interactive 3D viewer (auto-loads and highlights position 48)A48V_variant_card.md— this cardA48V_variant_card.html— demo-ready styled version
Final Schema Categorization
Category 5 — IDR EXCLUSION (DynaMut2 result is NOT trustworthy)
DynaMut2 returned a routine-looking -0.75 kcal/mol. That number should not be used clinically. The starting AlphaFold structure at position 48 has pLDDT 25.08 — well below the 50 threshold below which the model's local geometry is essentially noise. DynaMut2 assumes a meaningful input structure; for IDR residues that assumption is violated. Combined with AlphaMissense 0.075 (benign) and ClinVar's Conflicting clinical classifications, A48V is the Atlas's textbook 'I don't know — route to wet-lab' case. The schema's intellectual honesty matters most here.
Every assumption documented. Every score sourced. The Atlas standard.
Feed this card to Wolfram Intelligence
Download the A48V 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.