A31G
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialAlanine → Glycine at position 31 in wolframin's N-terminal intrinsically disordered region (IDR). ClinVar carries conflicting classifications. AlphaMissense 0.100 (likely BENIGN). pLDDT 28 — deep IDR. DynaMut2 ΔΔG -0.35 kcal/mol but NOT trustworthy. A Category 5 IDR variant flagged for wet-lab validation.
Interactive 3D Structure
Computational Predictions
- pLDDT 28.33 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 for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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 African / African American: AF 0.107% (80 of 74,724 alleles), 15.3x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| African / African American | 0.107% | 80 / 74,724 | 0 | ~1 in 470 |
| Admixed American | 0.018% | 10 / 56,672 | 0 | ~1 in 2830 |
| Remaining individuals | 0.0097% | 6 / 61,644 | 0 | ~1 in 5140 |
| European (non-Finnish) | 0.0013% | 15 / 1,168,866 | 0 | ~1 in 38960 |
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.
Structural Context
Position 31 sits in wolframin's N-terminal IDR. The pLDDT score of 28 indicates that AlphaFold cannot reliably predict the local conformation — the protein adopts an ensemble of structures in this region rather than a single fold. Neighbor analysis returns only the immediate sequence neighbors (SER32 at 2.5 Å, THR30 at 2.6 Å, LEU33 at 4.6 Å) — the structural signature of IDR.
Replacing alanine with glycine adds backbone flexibility. Glycine permits backbone conformations (especially in the Ramachandran left-handed helix region) that other amino acids cannot adopt. In a folded protein this is sometimes structurally significant. In an IDR, where the protein is already conformationally heterogeneous, the impact is more subtle — the ensemble's accessible conformational space shifts slightly, but no single 'wild-type' geometry is being broken.
DynaMut2's |ΔΔG| of 0.35 kcal/mol is not interpretable as a quantitative claim in this region. AlphaMissense's 0.100 score (well below the 0.564 pathogenic threshold) considers the variant likely benign.
The conflicting ClinVar classifications — some pathogenic, some uncertain — likely reflect that this variant has been observed in patients with Wolfram-spectrum disease but causal contribution has not been firmly established. The mechanism, if pathogenic, would likely involve IDR-mediated phase separation, partner binding through disordered regions, or context-dependent functional disruption — none of which AlphaMissense's training reliably captures.
Druggability Assessment
The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery. For A31G specifically, the recommended next steps are: (1) verify the clinical association with case-by-case review; (2) characterize the IDR's functional role; (3) test the variant in functional assays. Therapeutic strategy decisions should not be made on the current computational data alone.
Why this matters
Feed this card to Wolfram Intelligence
Download the A31G 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.