R139H
AlphaMissense: likely benign (0.21)Uncertain significanceCytoplasmic · predictedInteractive 3D Structure
Computational Predictions
AlphaMissense + AlphaFold card. This variant is mapped from AlphaMissense pathogenicity and AlphaFold confidence. The DynaMut2 ΔΔG stability prediction and the wild-type/mutant structural comparison (dual-pane + bond network) are computed per-variant and backfill here — they require a DynaMut2 submission, unlike the precomputed AlphaMissense score.
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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.013% (149 of 1,166,392 alleles), in line with the global figure.
1 homozygote reported in gnomAD v4 (1 South Asian). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.013% | 149 / 1,166,392 | 0 | ~1 in 3910 |
| Remaining individuals | 0.0081% | 5 / 61,446 | 0 | ~1 in 6140 |
| South Asian | 0.0023% | 2 / 86,692 | 1 | ~1 in 21670 |
| Admixed American · under-sampled | 0.0018% | 1 / 55,556 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,424 | 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
R139H — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Arginine (R) → Histidine (H) at position 139 Domain context: N-terminal cytoplasmic (intrinsically disordered)
AlphaMissense
- Pathogenicity score: 0.2098
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 139: 87.88
DynaMut2 ΔΔG: not yet computed for this variant — AlphaMissense + AlphaFold confidence shown above. Stability ΔΔG and the wild-type/mutant structural comparison backfill behind this note.
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.
- Classification: Uncertain significance
- Review status: criteria provided, multiple submitters, no conflicts
- cDNA change: c.416G>A
- ClinVar accession: VCV001200124
- Last evaluated: 2025/09/16 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.371310Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the R139H 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.