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G728=

SynonymousSilentLikely benignLumenal · predicted
Synonymous variant · codon at position 728 · 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
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AlphaFold wild-type wolframin · the variant site near residue 728 (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 (G728 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 conditionsWFS1-Related Spectrum Disorders; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1
Population frequency (gnomAD v4)Low frequency · AF 0.321%
cDNA changec.2184C>T
Protein consequenceG728=
ClinVar variantNM_006005.3(WFS1):c.2184C>T (p.Gly728=)
ClinVar accessionVCV000045448
Last evaluated2026/02/01 00:00

Observed in the general population.

Classified for2★ documented assertion

ClinVar classifies this variant as Benign/Likely benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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
  • Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
  • Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
  • 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 0.321% · 5,173 / 1,612,718 alleles
Homozygotes
154
Highest-frequency population
South Asian · AF 4.46%

Highest in South Asian: AF 4.46% (4064 of 91,060 alleles), 13.9x the global figure. The global AF describes the general population, not the at-risk group.

154 homozygotes reported in gnomAD v4 (146 South Asian; 4 Finnish; 4 Remaining individuals). 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.
South Asian4.46%4,064 / 91,060146~1 in 11
Finnish0.908%570 / 62,7804~1 in 55
Remaining individuals0.435%272 / 62,4804~1 in 110
Middle Eastern0.165%10 / 6,0620~1 in 300
European (non-Finnish)0.020%241 / 1,179,8980~1 in 2450
East Asian0.020%9 / 44,8640~1 in 2490
Admixed American0.0083%5 / 60,0020~1 in 6000
African / African American0.0027%2 / 75,0660~1 in 18770

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 G728= 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

G728= — WFS1 Molecular Atlas Card

Variant type: Synonymous (silent) Codon: position 728 (Glycine, G) — 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 (G728 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 WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)

ClinVar classifies this variant as Benign/Likely benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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.

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: WFS1-Related Spectrum Disorders; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1
  • cDNA change: c.2184C>T
  • ClinVar accession: VCV000045448
  • Last evaluated: 2026/02/01 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:55:52.600118Z. WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.