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N500=

SynonymousSilentConflictingTransmembrane · predicted
Synonymous variant · codon at position 500 · Transmembrane helix 7 · WFS1 (Wolframin)

Silent — Silent — no amino-acid change

Interactive 3D Structure

Interactive structure
rotate · zoom · variant + 5 Å neighbors
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AlphaFold wild-type wolframin · the variant site near residue 500 (Transmembrane helix 7) is highlighted.

Variant Assessment

Variant type
Synonymous
Schema
Silent
Silent — no amino-acid change
Domain
Transmembrane helix 7
Status
—

Therapeutic Implication · Silent

No amino-acid change (N500 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

ClinVar classificationConflicting classifications of pathogenicity
Review statuscriteria provided, conflicting classifications
Associated conditionsWFS1-Related Spectrum Disorders; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.1500C>T
Protein consequenceN500=
ClinVar variantNM_006005.3(WFS1):c.1500C>T (p.Asn500=)
ClinVar accessionVCV000045437
Last evaluated2026/02/04 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Classified for1★ unverified submission

ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); 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
  • WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
  • Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
  • 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.

Population frequency
Global (all ancestries)
Absent from gnomAD v4
Homozygotes
Not available

No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.

No homozygotes — the variant is absent from gnomAD v4 altogether.

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.

Therapeutic Strategy Handoff · prediction

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Full Variant Card

N500= — WFS1 Molecular Atlas Card

Variant type: Synonymous (silent) Codon: position 500 (Asparagine, N) — amino acid unchanged Domain context: Transmembrane helix 7

Schema category: Silent — Silent — no amino-acid change

No amino-acid change (N500 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 WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965)

ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); 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.

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: WFS1-Related Spectrum Disorders; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6
  • cDNA change: c.1500C>T
  • ClinVar accession: VCV000045437
  • Last evaluated: 2026/02/04 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:54:01.975233Z. WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.