R611H
AlphaMissense: likely benign (0.09)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); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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
- 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 East Asian: AF 84.29% (37793 of 44,838 alleles), in line with the global figure.
240154 homozygotes reported in gnomAD v4 (15969 East Asian; 6006 Ashkenazi Jewish; 11827 Admixed American; 14995 South Asian; 173045 European (non-Finnish); 9228 Remaining individuals; 810 Middle Eastern; 7739 Finnish; 63 Amish; 472 African / African American). 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 | 84.29% | 37,793 / 44,838 | 15969 | ~1 in 1 |
| Ashkenazi Jewish | 63.82% | 18,896 / 29,608 | 6006 | ~1 in 1 |
| Admixed American | 62.11% | 37,277 / 60,020 | 11827 | ~1 in 1 |
| South Asian | 56.88% | 51,802 / 91,068 | 14995 | ~1 in 1 |
| European (non-Finnish) | 54.17% | 639,149 / 1,179,916 | 173045 | ~1 in 1 |
| Remaining individuals | 53.68% | 33,549 / 62,502 | 9228 | ~1 in 1 |
| Middle Eastern | 50.08% | 3,036 / 6,062 | 810 | ~1 in 1 |
| Finnish | 48.89% | 31,252 / 63,924 | 7739 | ~1 in 1 |
| Amish | 36.40% | 332 / 912 | 63 | ~1 in 1 |
| African / African American | 9.99% | 7,491 / 75,014 | 472 | ~1 in 5 |
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
R611H — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Arginine (R) → Histidine (H) at position 611 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
AlphaMissense
- Pathogenicity score: 0.0882
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 611: 58.38
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); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
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); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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; Wolfram syndrome 1
- cDNA change: c.1832G>A
- ClinVar accession: VCV000045442
- Last evaluated: 2026/02/04 00:00
- Submissions: 2
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.659344Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the R611H 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.