A874=
SynonymousSilentLikely benignTransmembrane · predictedSilent — Silent — no amino-acid change
Interactive 3D Structure
AlphaFold wild-type wolframin · the variant site near residue 874 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted.
Variant Assessment
Therapeutic Implication · Silent
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Benign/Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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 0.217% (163 of 75,060 alleles), 15.3x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (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. |
|---|---|---|---|---|
| African / African American | 0.217% | 163 / 75,060 | 1 | ~1 in 230 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| Remaining individuals | 0.014% | 9 / 62,498 | 0 | ~1 in 3470 |
| East Asian | 0.013% | 6 / 44,884 | 0 | ~1 in 3740 |
| European (non-Finnish) | 0.0037% | 44 / 1,180,044 | 0 | ~1 in 13410 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,606 | 0 | — |
| South Asian | 0.0033% | 3 / 91,090 | 0 | ~1 in 15180 |
| Admixed American · under-sampled | 0.0017% | 1 / 60,026 | 0 | — |
| Finnish · under-sampled | 0.0016% | 1 / 63,002 | 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.
Feed this card to Wolfram Intelligence
Download the A874= 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
A874= — WFS1 Molecular Atlas Card
Variant type: Synonymous (silent) Codon: position 874 (Alanine, A) — amino acid unchanged Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Schema category: Silent — Silent — no amino-acid change
No amino-acid change (A874 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/Likely benign — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296)
ClinVar classifies this variant as Benign/Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
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; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Cataract 41; Wolfram-like syndrome
- cDNA change: c.2622C>T
- ClinVar accession: VCV000378861
- Last evaluated: 2026/01/15 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:56:57.060705Z.
WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.