Y669C
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialTyrosine → Cysteine at position 669 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, associated with classical autosomal recessive Wolfram syndrome 1. AlphaMissense 0.998, DynaMut2 ΔΔG -0.41 kcal/mol (destabilising). One of the six pilot variants in the Atlas.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T665 | T665 | Preserved |
| Hydrogen bond | — | W666 | Gained |
| Hydrogen bond | L672 | L672 | Preserved |
| Hydrogen bond | C673 | C673 | Preserved |
| Hydrogen bond | G834 | — | Lost |
| Polar contact | T665 | T665 | Preserved |
| Polar contact | W666 | W666 | Preserved |
| Polar contact | A671 | — | Lost |
| Polar contact | L672 | L672 | Preserved |
| Polar contact | C673 | C673 | Preserved |
| Polar contact | L833 | — | Lost |
| Polar contact | G834 | — | Lost |
| Aromatic / π | W666 | — | Lost |
| Aromatic / π | W700 | — | Lost |
| Van der Waals | A671 | A671 | Preserved |
| Van der Waals | C673 | C673 | Preserved |
| Hydrophobic | L664 | L664 | Preserved |
| Hydrophobic | W666 | W666 | Preserved |
| Hydrophobic | C673 | — | Lost |
| Hydrophobic | L693 | — | Lost |
| Hydrophobic | W700 | W700 | Preserved |
| Hydrophobic | L829 | — | Lost |
| Hydrophobic | L833 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic 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
- This rests on a single submitter (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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00018% (2 of 1,111,992 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00018% | 2 / 1,111,992 | 0 | ~1 in 278000 |
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.
Structural Context
Position 669 sits in wolframin's C-terminal lumenal domain (residues 653–869). The AlphaFold model places Y669 within 5 Å of GLN668 (2.5 Å), GLY670 (2.5 Å), TRP666 (3.8 Å), THR665 (4.0 Å), ALA671 (4.4 Å), and GLN667 (4.5 Å). The wild-type tyrosine ring sits in an aromatic-adjacent environment — TRP666 at 3.8 Å is consistent with edge-face π–π stacking between the Y669 phenol and the W666 indole. The hydroxyl group of the wild-type also makes plausible hydrogen-bonding contacts to GLN668 and THR665.
Replacing tyrosine with cysteine at this position has three layered effects. First, the aromatic ring is gone, eliminating the π-stacking with TRP666 and the hydrophobic surface contributed to the local fold. Second, the hydroxyl group is gone, removing two hydrogen-bond contacts. Third, a reactive free thiol is introduced into the oxidizing ER lumen — and the lumenal domain contains other cysteine residues (notably CYS673 at 3.8 Å from C690, a separate position) that could engage in aberrant disulfide formation. The new C669 is not directly in contact with another cysteine in the AlphaFold model, but disulfide chemistry in an oxidizing compartment is promiscuous.
DynaMut2 returns a modest |ΔΔG| of 0.41 kcal/mol. The fold survives the substitution. The damage is mechanistic — lost aromatic packing, lost H-bonding, plus the off-pathway disulfide risk that DynaMut2's structural prediction cannot fully capture.
Druggability Assessment
The mechanism is layered: aromatic stacking with TRP666 broken, hydrogen bonding to GLN668/THR665 lost, and a new free thiol introduced into a compartment where it can form aberrant disulfides. Site-directed small molecules that occupy the lost aromatic packing footprint and/or block the introduced thiol are the rational therapeutic vector.
Compare with Y669H at the same position (Atlas card adjacent): Y669H preserves more of the aromatic character but introduces titratable basicity, and shows a stronger ΔΔG of -1.2 kcal/mol. The two variants together illustrate how substitution chemistry at a single position drives different mechanism and severity.
Why this matters
Feed this card to Wolfram Intelligence
Download the Y669C PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.