RareResearch.AI
← Back to atlas

L734=

SynonymousSilentLikely benignLumenal · predicted
Synonymous variant · codon at position 734 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Silent — Silent — no amino-acid change

Interactive 3D Structure

Interactive structure
rotate · zoom · variant + 5 Å neighbors
Fullscreen ↗

AlphaFold wild-type wolframin · the variant site near residue 734 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted.

Variant Assessment

Variant type
Synonymous
Schema
Silent
Silent — no amino-acid change
Domain
C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Status
—

Therapeutic Implication · Silent

No amino-acid change (L734 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 classificationBenign/Likely benign
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Low frequency · AF 0.012%
cDNA changec.2202C>T
Protein consequenceL734=
ClinVar variantNM_006005.3(WFS1):c.2202C>T (p.Leu734=)
ClinVar accessionVCV000045450
Last evaluated2025/12/24 00:00

Observed in the general population.

Classified for2★ documented assertion

ClinVar classifies this variant as Benign/Likely benign 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
  • 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.

Population frequency
Global (all ancestries)
AF 0.012% · 194 / 1,612,698 alleles
Homozygotes
2
Highest-frequency population
African / African American · AF 0.128%

Highest in African / African American: AF 0.128% (96 of 75,060 alleles), 10.6x the global figure. The global AF describes the general population, not the at-risk group.

2 homozygotes reported in gnomAD v4 (1 African / African American; 1 Admixed 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 groupAllele freq.AC / ANHom.Carrier est.
African / African American0.128%96 / 75,0601~1 in 390
Middle Eastern0.050%3 / 6,0600~1 in 1010
Admixed American0.037%22 / 59,9861~1 in 1360
Remaining individuals0.032%20 / 62,4820~1 in 1560
European (non-Finnish)0.0045%53 / 1,179,9200~1 in 11130

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

Feed this card to Wolfram Intelligence

Download the L734= card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this Silent synonymous variant and its domain context.

Download L734= PDF card ↓or markdown ↓

Full Variant Card

L734= — WFS1 Molecular Atlas Card

Variant type: Synonymous (silent) Codon: position 734 (Leucine, L) — 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 (L734 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)

ClinVar classifies this variant as Benign/Likely benign 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.

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
  • cDNA change: c.2202C>T
  • ClinVar accession: VCV000045450
  • Last evaluated: 2025/12/24 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:55:54.895335Z. WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.