I561=
SynonymousSilentBenignCytoplasmic · predictedSilent — Silent — no amino-acid change
Interactive 3D Structure
AlphaFold wild-type wolframin · the variant site near residue 561 (Lumenal loop 4) is highlighted.
Variant Assessment
Therapeutic Implication · Silent
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as 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 South Asian: AF 4.47% (4073 of 91,078 alleles), 15.6x the global figure. The global AF describes the general population, not the at-risk group.
153 homozygotes reported in gnomAD v4 (148 South Asian; 4 Remaining individuals; 1 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. |
|---|---|---|---|---|
| South Asian | 4.47% | 4,073 / 91,078 | 148 | ~1 in 11 |
| Remaining individuals | 0.445% | 278 / 62,500 | 4 | ~1 in 110 |
| Middle Eastern | 0.330% | 20 / 6,062 | 0 | ~1 in 150 |
| African / African American | 0.214% | 161 / 75,066 | 1 | ~1 in 230 |
| Admixed American | 0.040% | 24 / 60,030 | 0 | ~1 in 1250 |
| East Asian | 0.027% | 12 / 44,882 | 0 | ~1 in 1870 |
| European (non-Finnish) | 0.0043% | 51 / 1,180,044 | 0 | ~1 in 11570 |
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.
Feed this card to Wolfram Intelligence
Download the I561= card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this Silent synonymous variant and its domain context.
Full Variant Card
I561= — WFS1 Molecular Atlas Card
Variant type: Synonymous (silent) Codon: position 561 (Isoleucine, I) — amino acid unchanged Domain context: Lumenal loop 4
Schema category: Silent — Silent — no amino-acid change
No amino-acid change (I561 is unchanged): the codon is altered but the protein sequence is identical to wild-type. No structural, stability or AlphaMissense effect applies. Synonymous variants are typically benign unless they affect splicing or regulatory elements; this one is not adjacent to an exon boundary.
Clinical evidence
Inheritance and scope
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 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
- 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.1683C>T
- ClinVar accession: VCV000166595
- Last evaluated: 2026/02/01 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:54:39.396769Z.
WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.