C690Y
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialCysteine → Tyrosine at position 690 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic with the full clinical spectrum documented — Wolfram syndrome 1, Wolfram-like syndrome, DFNA6 hearing loss, type 2 diabetes, and cataract 41. AlphaMissense 0.999, DynaMut2 ΔΔG -1.16 kcal/mol (destabilising). A high-pathogenicity, high-clinical-impact variant.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | Y669 | Gained |
| Hydrogen bond | T686 | T686 | Preserved |
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | L693 | — | Lost |
| Hydrogen bond | — | L829 | Gained |
| Hydrogen bond | — | L833 | Gained |
| Polar contact | — | Y669 | Gained |
| Polar contact | C673 | C673 | Preserved |
| Polar contact | T686 | T686 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | — | I688 | Gained |
| Polar contact | H692 | — | Lost |
| Polar contact | L693 | L693 | Preserved |
| Polar contact | — | L829 | Gained |
| Polar contact | L833 | L833 | Preserved |
| Aromatic / π | — | Y669 | Gained |
| Carbonyl | — | Q687 | Gained |
| Van der Waals | — | C673 | Gained |
| Van der Waals | — | Q687 | Gained |
| Van der Waals | L833 | L833 | Preserved |
| Hydrophobic | — | Y669 | Gained |
| Hydrophobic | C673 | C673 | Preserved |
| Hydrophobic | — | L693 | Gained |
| Hydrophobic | L833 | L833 | Preserved |
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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 690 sits in wolframin's C-terminal lumenal domain (residues 653–869), the protein's largest soluble region and the primary site of documented protein-protein interactions with ATF6 and Na+/K+ ATPase β1. The AlphaFold model places C690 within 5 Å of: LEU689 (2.5 Å), SER691 (2.5 Å), THR686 (3.7 Å), GLN687 (3.8 Å), CYS673 (3.8 Å), HIS692 (4.2 Å), ILE688 (4.6 Å), and LEU833 (4.7 Å).
The most structurally consequential of these is CYS673 at 3.8 Å. This spacing is consistent with a structural disulfide bond between C690 and C673 in the lumenal fold — an oxidative-environment crosslink that locks two distant segments of the domain together. The C690Y substitution eliminates the cysteine thiol, breaking any such disulfide, and replaces it with a bulky aromatic ring carrying a hydroxyl group.
Replacing cysteine with tyrosine here has three layered effects: (1) the disulfide crosslink is lost; (2) a substantial volume increase from the aromatic ring would either displace surrounding residues or be sterically disallowed in the wild-type geometry, forcing local rearrangement; (3) the tyrosine hydroxyl introduces new hydrogen-bonding potential that could either compensate (by H-bonding to GLN687, THR686, or SER691) or further perturb the local network. The DynaMut2 |ΔΔG| of 1.16 kcal/mol indicates the net effect is moderate — the fold can absorb the substitution, but at energetic cost — while the AlphaMissense score of 0.999 indicates the functional consequence is severe.
Comparison with C690R (the same position with arginine substitution, also in the Atlas) is instructive: both substitutions break the inferred C690-C673 disulfide, but the tyrosine variant introduces aromatic packing where the arginine introduces charge. The two yield similar |ΔΔG| (1.16 vs 1.29) but differ in their downstream therapeutic implications.
Druggability Assessment
The mechanism combines disulfide loss (the C690-C673 inferred crosslink) with steric and electronic perturbation from the introduced aromatic ring. This is a defined, local lesion in a folded protein — exactly the profile that responds to site-directed small-molecule therapy. The drug-discovery question becomes: can we identify a compound that occupies the C690 site, restores the geometry of the surrounding pocket, and partially compensates for the lost C673 contact?
The clinical breadth of this variant (five documented phenotypes across both AD and AR inheritance) makes it one of the highest-value docking targets in the Atlas. A small molecule that rescues C690Y has potential clinical reach across the entire WFS1 patient population — not just Wolfram syndrome 1 carriers.
Why this matters
Feed this card to Wolfram Intelligence
Download the C690Y 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.