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G581=

SynonymousSilentConflictingTransmembrane · predicted
Synonymous variant · codon at position 581 · Transmembrane helix 9 · 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 581 (Transmembrane helix 9) is highlighted.

Variant Assessment

Variant type
Synonymous
Schema
Silent
Silent — no amino-acid change
Domain
Transmembrane helix 9
Status
—

Therapeutic Implication · Silent

No amino-acid change (G581 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 conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.0071%
cDNA changec.1743C>T
Protein consequenceG581=
ClinVar variantNM_006005.3(WFS1):c.1743C>T (p.Gly581=)
ClinVar accessionVCV000166596
Last evaluated2025/07/04 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

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.

Population frequency
Global (all ancestries)
AF 0.0071% · 115 / 1,613,992 alleles
Homozygotes
0
Highest-frequency population
Admixed American · AF 0.045%

Highest in Admixed American: AF 0.045% (27 of 60,032 alleles), 6.3x the global figure. The global AF describes the general population, not the at-risk group.

No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.

Ancestry groupAllele freq.AC / ANHom.Carrier est.
Admixed American0.045%27 / 60,0320~1 in 1110
European (non-Finnish)0.0071%84 / 1,180,0420~1 in 7020
Remaining individuals0.0048%3 / 62,5020~1 in 10420
South Asian · under-sampled0.0011%1 / 91,0760—

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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Download the G581= card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this Silent synonymous variant and its domain context.

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Full Variant Card

G581= — WFS1 Molecular Atlas Card

Variant type: Synonymous (silent) Codon: position 581 (Glycine, G) — amino acid unchanged Domain context: Transmembrane helix 9

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

No amino-acid change (G581 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.1743C>T
  • ClinVar accession: VCV000166596
  • Last evaluated: 2025/07/04 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:54:53.255545Z. WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.