Y650H
Category 4 — Stable Fold, Function DisruptedPathogenicTransmembrane · predictedEditorialTyrosine → Histidine at position 650 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic. AlphaMissense 0.518 (AMBIGUOUS — at the likely-pathogenic threshold), DynaMut2 ΔΔG +0.05 kcal/mol (essentially neutral). pLDDT 69 — borderline confidence. A variant in a confidence-edge region with ambiguous AM signal but confirmed clinical pathogenicity.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I338 | — | Lost |
| Hydrogen bond | F646 | F646 | Preserved |
| Hydrogen bond | C647 | C647 | Preserved |
| Hydrogen bond | R653 | — | Lost |
| Hydrogen bond | S654 | S654 | Preserved |
| Polar contact | F646 | F646 | Preserved |
| Polar contact | C647 | C647 | Preserved |
| Polar contact | W648 | W648 | Preserved |
| Polar contact | Y652 | — | Lost |
| Polar contact | R653 | R653 | Preserved |
| Polar contact | S654 | S654 | Preserved |
| Van der Waals | W648 | W648 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 650 sits near the end of TM10. The AlphaFold model places Y650 within 5 Å of PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å), PHE646 (3.7 Å), and TRP648 (4.4 Å). The local environment is dominated by aromatic residues (F649, F646, W648) plus a cysteine (C647) — a tightly-packed aromatic cluster at the end of TM10.
The wild-type tyrosine ring participates in π-stacking with the surrounding aromatic residues (F649, F646, W648). The hydroxyl can H-bond to C647's backbone or to a nearby polar residue. The local environment is densely aromatic — a structural feature that requires precise geometric matching.
Replacing tyrosine with histidine preserves some aromatic character (histidine's imidazole is aromatic) but the geometry shifts substantially. Histidine's imidazole is smaller and oriented differently than tyrosine's phenol. The π-stacking pattern with F649/F646/W648 reorganizes.
The DynaMut2 ΔΔG of essentially zero (+0.05) indicates fold accommodates the swap easily — both residues fit in the local pocket. But AlphaMissense's 0.518 is borderline (just below the 0.564 likely-pathogenic threshold), and ClinVar Pathogenic + the borderline pLDDT (69) together create an ambiguous interpretation.
The variant is likely pathogenic by a specific mechanism (disrupted aromatic stacking geometry in the TM10 C-terminal aromatic cluster) but the AM signal is weak. This is a variant where wet-lab characterization would be especially valuable.
Druggability Assessment
The mechanism is reorganization of an aromatic stacking cluster (F646, F649, W648) at the C-terminal end of TM10. Therapeutic strategy: site-directed at the TM10 aromatic cluster. Wet-lab characterization is strongly recommended before therapeutic strategy is finalized given the AM and pLDDT borderline signals.
Why this matters
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