V441M
AlphaMissense: likely benign (0.12)Likely benignTransmembrane · 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 in the general population.
ClinVar classifies this variant as Benign/Likely benign 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
- 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 African / African American: AF 0.276% (207 of 75,006 alleles), 17.1x 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 | 0.276% | 207 / 75,006 | 0 | ~1 in 180 |
| Admixed American | 0.045% | 27 / 60,018 | 0 | ~1 in 1110 |
| Remaining individuals | 0.026% | 16 / 62,502 | 0 | ~1 in 1950 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| South Asian | 0.0033% | 3 / 91,074 | 0 | ~1 in 15180 |
| East Asian · under-sampled | 0.0022% | 1 / 44,868 | 0 | — |
| European (non-Finnish) | 0.00042% | 5 / 1,180,018 | 0 | ~1 in 118000 |
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
V441M — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Valine (V) → Methionine (M) at position 441 Domain context: Transmembrane helix 5
AlphaMissense
- Pathogenicity score: 0.1169
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 441: 89.12
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
Benign/Likely benign — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Benign/Likely benign 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.
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: Benign/Likely benign
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.1321G>A
- ClinVar accession: VCV000178591
- Last evaluated: 2026/01/16 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.534963Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the V441M 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.