V333I
AlphaMissense: likely benign (0.05)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
Population frequency too high for a penetrant Wolfram allele — stand-alone benign evidence (ACMG BA1).
ClinVar classifies this variant as Benign/Likely benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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 East Asian: AF 99.79% (44757 of 44,850 alleles), in line with the global figure.
457955 homozygotes reported in gnomAD v4 (22332 East Asian; 34286 African / African American; 31823 South Asian; 9777 Ashkenazi Jewish; 19561 Admixed American; 1961 Middle Eastern; 18913 Remaining individuals; 305011 European (non-Finnish); 14144 Finnish; 147 Amish). 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. |
|---|---|---|---|---|
| East Asian | 99.79% | 44,757 / 44,850 | 22332 | ~1 in 1 |
| African / African American | 95.61% | 71,657 / 74,950 | 34286 | ~1 in 1 |
| South Asian | 83.43% | 75,962 / 91,050 | 31823 | ~1 in 1 |
| Ashkenazi Jewish | 81.19% | 24,035 / 29,604 | 9777 | ~1 in 1 |
| Admixed American | 80.63% | 48,370 / 59,990 | 19561 | ~1 in 1 |
| Middle Eastern | 79.79% | 4,837 / 6,062 | 1961 | ~1 in 1 |
| Remaining individuals | 77.55% | 48,471 / 62,504 | 18913 | ~1 in 1 |
| European (non-Finnish) | 71.89% | 848,240 / 1,179,922 | 305011 | ~1 in 1 |
| Finnish | 66.43% | 42,494 / 63,966 | 14144 | ~1 in 1 |
| Amish | 58.59% | 532 / 908 | 147 | ~1 in 1 |
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
V333I — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Valine (V) → Isoleucine (I) at position 333 Domain context: Cytoplasmic loop 1
AlphaMissense
- Pathogenicity score: 0.0465
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 333: 71.5
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 WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400)
ClinVar classifies this variant as Benign/Likely benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
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: WFS1-Related Spectrum Disorders; Wolfram syndrome 1; Wolfram-like syndrome; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6; Cataract 41
- cDNA change: c.997G>A
- ClinVar accession: VCV000045463
- Last evaluated: 2026/02/04 00:00
- Submissions: 2
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.465645Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the V333I 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.