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T436=

SynonymousSilentBenignTransmembrane · predicted
Synonymous variant · codon at position 436 · Transmembrane helix 5 · 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 436 (Transmembrane helix 5) is highlighted.

Variant Assessment

Variant type
Synonymous
Schema
Silent
Silent — no amino-acid change
Domain
Transmembrane helix 5
Status
—

Therapeutic Implication · Silent

No amino-acid change (T436 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
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWFS1-Related Spectrum Disorders; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.1308C>T
Protein consequenceT436=
ClinVar variantNM_006005.3(WFS1):c.1308C>T (p.Thr436=)
ClinVar accessionVCV000045433
Last evaluated2026/03/01 00:00

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

Classified for2★ documented assertion

ClinVar classifies this variant as Benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); 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
  • Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
  • Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
  • 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)
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

T436= — WFS1 Molecular Atlas Card

Variant type: Synonymous (silent) Codon: position 436 (Threonine, T) — amino acid unchanged Domain context: Transmembrane helix 5

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

No amino-acid change (T436 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 — for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965)

ClinVar classifies this variant as Benign for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); 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.

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
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: WFS1-Related Spectrum Disorders; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6
  • cDNA change: c.1308C>T
  • ClinVar accession: VCV000045433
  • Last evaluated: 2026/03/01 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:53:17.850840Z. WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.