K774=
SynonymousSilentBenignLumenal · predictedSilent — Silent — no amino-acid change
Interactive 3D Structure
AlphaFold wild-type wolframin · the variant site near residue 774 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted.
Variant Assessment
Therapeutic Implication · Silent
Clinical Evidence
Population frequency too high for a penetrant Wolfram allele — stand-alone benign evidence (ACMG BA1).
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.
Highest in Amish: AF 17.98% (164 of 912 alleles), 2.5x the global figure. The global AF describes the general population, not the at-risk group.
4881 homozygotes reported in gnomAD v4 (20 Amish; 58 Middle Eastern; 599 South Asian; 145 Ashkenazi Jewish; 230 African / African American; 3575 European (non-Finnish); 177 Remaining individuals; 50 Admixed American; 27 Finnish). 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 group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Amish | 17.98% | 164 / 912 | 20 | ~1 in 3 |
| Middle Eastern | 12.47% | 756 / 6,062 | 58 | ~1 in 4 |
| South Asian | 10.64% | 9,691 / 91,088 | 599 | ~1 in 5 |
| Ashkenazi Jewish | 9.29% | 2,751 / 29,598 | 145 | ~1 in 5 |
| African / African American | 7.73% | 5,801 / 75,056 | 230 | ~1 in 6 |
| European (non-Finnish) | 7.67% | 90,526 / 1,180,012 | 3575 | ~1 in 7 |
| Remaining individuals | 7.17% | 4,480 / 62,496 | 177 | ~1 in 7 |
| Admixed American | 3.95% | 2,371 / 60,034 | 50 | ~1 in 13 |
| Finnish | 2.84% | 1,783 / 62,788 | 27 | ~1 in 18 |
| East Asian | 0.053% | 24 / 44,878 | 0 | ~1 in 930 |
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.
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Full Variant Card
K774= — WFS1 Molecular Atlas Card
Variant type: Synonymous (silent) Codon: position 774 (Lysine, K) — 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 (K774 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.2322G>A
- ClinVar accession: VCV000045452
- Last evaluated: 2026/02/03 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (synonymous pipeline) on 2026-06-08T02:56:09.180953Z.
WFS1: UniProt O76024, AlphaFold v6. Synonymous variants carry no protein-structural effect.