G437S
AlphaMissense: likely benign (0.08)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 WFS1-related spectrum (unresolved mode) (dominant or recessive); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). 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
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- 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 0.426% (191 of 44,864 alleles), 24.6x the global figure. The global AF describes the general population, not the at-risk group.
2 homozygotes reported in gnomAD v4 (2 East 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. |
|---|---|---|---|---|
| East Asian | 0.426% | 191 / 44,864 | 2 | ~1 in 120 |
| Middle Eastern | 0.033% | 2 / 6,060 | 0 | ~1 in 1520 |
| Remaining individuals | 0.024% | 15 / 62,504 | 0 | ~1 in 2080 |
| South Asian | 0.018% | 16 / 91,076 | 0 | ~1 in 2850 |
| European (non-Finnish) | 0.0046% | 54 / 1,180,018 | 0 | ~1 in 10930 |
| African / African American · under-sampled | 0.0013% | 1 / 74,990 | 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
G437S — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Glycine (G) → Serine (S) at position 437 Domain context: Transmembrane helix 5
AlphaMissense
- Pathogenicity score: 0.0824
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 437: 90.31
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); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965)
ClinVar classifies this variant as Benign/Likely benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). 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; Autosomal dominant nonsyndromic hearing loss 6
- cDNA change: c.1309G>A
- ClinVar accession: VCV000215356
- Last evaluated: 2026/03/13 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.533112Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the G437S 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.