L565=
SynonymousSilentConflictingTransmembrane · predictedSilent — Silent — no amino-acid change
Interactive 3D Structure
AlphaFold wild-type wolframin · the variant site near residue 565 (Lumenal loop 4) is highlighted.
Variant Assessment
Therapeutic Implication · Silent
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.016% (189 of 1,179,916 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Middle Eastern · under-sampled | 0.016% | 1 / 6,084 | 0 | — |
| European (non-Finnish) | 0.016% | 189 / 1,179,916 | 0 | ~1 in 3120 |
| Remaining individuals | 0.0080% | 5 / 62,470 | 0 | ~1 in 6250 |
| Admixed American | 0.0050% | 3 / 60,012 | 0 | ~1 in 10000 |
| Finnish | 0.0032% | 2 / 63,196 | 0 | ~1 in 15800 |
| African / African American · under-sampled | 0.0013% | 1 / 74,956 | 0 | — |
| South Asian · under-sampled | 0.0011% | 1 / 91,080 | 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.
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Full Variant Card
L565= — WFS1 Molecular Atlas Card
Variant type: Synonymous (silent) Codon: position 565 (Leucine, L) — amino acid unchanged Domain context: Lumenal loop 4
Schema category: Silent — Silent — no amino-acid change
No amino-acid change (L565 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
Conflicting classifications of pathogenicity — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes. 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: Conflicting classifications of pathogenicity
- Review status: criteria provided, conflicting classifications
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.1695C>T
- ClinVar accession: VCV000772341
- Last evaluated: 2025/12/01 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:54:42.247306Z.
WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.