R805W
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Tryptophan at position 805 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.487 (borderline), ΔΔG +0.26 STABILISING. R→W class — aromatic replaces charge.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E776 | — | Lost |
| Hydrogen bond | F775 | F775 | Preserved |
| Hydrogen bond | — | E776 | Gained |
| Hydrogen bond | F840 | F840 | Preserved |
| Hydrogen bond | E841 | E841 | Preserved |
| Hydrogen bond | L842 | L842 | Preserved |
| Polar contact | F775 | F775 | Preserved |
| Polar contact | E776 | E776 | Preserved |
| Polar contact | F840 | F840 | Preserved |
| Polar contact | L842 | L842 | Preserved |
| Van der Waals | — | E776 | Gained |
| Van der Waals | — | V839 | Gained |
| Hydrophobic | E776 | E776 | Preserved |
| Hydrophobic | V839 | V839 | 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
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 Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Admixed American: AF 0.0050% (3 of 59,972 alleles), 2.3x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 Admixed American). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Middle Eastern · under-sampled | 0.016% | 1 / 6,078 | 0 | — |
| Admixed American | 0.0050% | 3 / 59,972 | 1 | ~1 in 10000 |
| Finnish | 0.0048% | 3 / 62,314 | 0 | ~1 in 10390 |
| East Asian | 0.0045% | 2 / 44,864 | 0 | ~1 in 11220 |
| African / African American | 0.0040% | 3 / 74,918 | 0 | ~1 in 12490 |
| European (non-Finnish) | 0.0019% | 22 / 1,178,998 | 0 | ~1 in 26800 |
| South Asian · under-sampled | 0.0011% | 1 / 90,992 | 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 805 in lumenal domain. Neighbors: ALA806 (2.4 Å — A806P), LEU804 (2.5 Å — L804P!), PHE775 (3.4 Å — F775V!), PHE840 (3.7 Å).
R805 sits in the dense 804-806 cluster (with L804P, A806P) and contacts F775 (F775V). Replacing R805 with tryptophan eliminates the positive charge and creates a tryptophan-phenylalanine aromatic cluster with F775 + F840. The variant fold packs efficiently (+0.26).
AM 0.487 borderline; ClinVar Conflicting. The mechanism is loss of R805 charge from the F775-R805 ionic/cation-π contact discussed in F775V Atlas card.
Druggability Assessment
Mechanism: loss of R805 cation-π contribution to F775 contact. Therapeutic: same 775-806 microregion (with L804P, A806P, F775V).
Why this matters
Feed this card to Wolfram Intelligence
Download the R805W 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.