R629W
Category 4 — Stable Fold, Function DisruptedPathogenicTransmembrane · predictedEditorialArginine → Tryptophan at position 629 in a connecting loop. ClinVar Pathogenic, associated with classical Wolfram syndrome 1. AlphaMissense 0.181 (deep BENIGN range), DynaMut2 ΔΔG -0.56 kcal/mol (destabilising). pLDDT 60 — borderline. A puzzling variant: ClinVar says pathogenic, AM says benign, ΔΔG is mild.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S626 | S626 | Preserved |
| Hydrogen bond | M632 | M632 | Preserved |
| Polar contact | S626 | S626 | Preserved |
| Polar contact | L627 | L627 | Preserved |
| Polar contact | S631 | S631 | Preserved |
| Polar contact | M632 | M632 | Preserved |
| Van der Waals | L627 | L627 | Preserved |
| Van der Waals | S631 | — | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 629 sits in a connecting loop region. The AlphaFold model places R629 within 5 Å of THR628 (2.5 Å), SER630 (2.5 Å), SER626 (3.8 Å), SER631 (4.3 Å), and LEU627 (4.5 Å). The local environment is unusually serine-rich (S630, S626, S631) — three serines within 5 Å — suggesting a polar loop region characterized by hydroxyl-mediated H-bonding.
The wild-type arginine at 629 likely engages this serine-rich environment through its long, basic side chain — H-bonding to the serine hydroxyls and possibly extending toward a partner protein for recognition.
Replacing arginine with tryptophan eliminates the positive charge and the long H-bond-donating side chain, replacing them with a bulky aromatic indole. The serine-rich local environment loses its arginine partner; the introduced tryptophan does not fit cleanly into a polar pocket.
The |ΔΔG| of 0.56 is modest. But AlphaMissense places this at 0.181 — deep in the likely-benign range. The discrepancy with ClinVar Pathogenic classification (associated with Wolfram syndrome 1) is similar to the W639G case. Possible explanations: AM under-calls pathogenicity for variants in low-confidence regions (pLDDT 60 here); the variant is pathogenic only in specific clinical contexts; or it has been clinically misclassified. The Atlas surfaces this complexity rather than resolving it.
Druggability Assessment
The mechanism, if pathogenic, is loss of an arginine-serine network in a polar loop region. Therapeutic strategy is genuinely uncertain given the AM-ClinVar disconnect and the pLDDT 60 borderline structural confidence.
This is a variant where wet-lab characterization is strongly recommended before any therapeutic strategy is set. The Atlas appropriately flags the conflict rather than over-confidently picking a side.
Why this matters
Feed this card to Wolfram Intelligence
Download the R629W 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.