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
- transmembrane position; predictor benchmarked on soluble proteins
- pLDDT 59.97 below 70
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as 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
- 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 Admixed American: AF 0.0083% (5 of 60,028 alleles), 3.1x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Admixed American | 0.0083% | 5 / 60,028 | 0 | ~1 in 6000 |
| African / African American | 0.0067% | 5 / 75,074 | 0 | ~1 in 7510 |
| Remaining individuals | 0.0032% | 2 / 62,506 | 0 | ~1 in 15630 |
| European (non-Finnish) | 0.0025% | 30 / 1,180,042 | 0 | ~1 in 19670 |
| Finnish · under-sampled | 0.0016% | 1 / 63,914 | 0 | — |
| South Asian · under-sampled | 0.0011% | 1 / 91,086 | 0 | — |
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 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.