A806P
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialProline substitution in a tightly packed C-terminal lumenal segment — backbone rigidity is introduced where the protein needs torsional freedom, and the ATF6-interacting sensor face takes the hit.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | K774 | — | Lost |
| Hydrogen bond | F775 | F775 | Preserved |
| Polar contact | F775 | F775 | Preserved |
| Polar contact | — | L804 | Gained |
| Van der Waals | — | F775 | Gained |
| Van der Waals | — | I777 | Gained |
| Van der Waals | — | L804 | Gained |
| Hydrophobic | F775 | F775 | Preserved |
| Hydrophobic | I777 | I777 | Preserved |
| Hydrophobic | F810 | F810 | Preserved |
| Hydrophobic | L814 | L814 | Preserved |
| Hydrophobic | L842 | L842 | 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 Pathogenic/Likely pathogenic, 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: 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 0.0045% (2 of 44,678 alleles), 13.1x 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 | 0.0045% | 2 / 44,678 | 0 | ~1 in 11170 |
| Remaining individuals · under-sampled | 0.0017% | 1 / 60,296 | 0 | — |
| European (non-Finnish) | 0.00018% | 2 / 1,110,848 | 0 | ~1 in 277710 |
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
A806 occupies a tightly packed region of the lumenal domain, framed by Ser807 (2.42 Angstrom), Arg805 (2.44 Angstrom), and an aromatic shell drawn in by Phe775 (3.82 Angstrom), Phe810 (4.09 Angstrom), and the aliphatic Leu842 (4.22 Angstrom) and Leu804 (4.82 Angstrom). The wild-type alanine's compact methyl side chain is tolerated here precisely because it does not perturb the backbone, leaving the phi/psi angles free to accommodate the local turn geometry that brings the Phe775-Phe810 aromatic pair into close register with the Arg805 guanidinium just one residue away.
Proline destroys that arrangement. Its pyrrolidine ring forces backbone phi near -60 degrees and eliminates the amide NH, which means the residue can no longer donate a hydrogen bond to upstream carbonyls and can no longer adopt the phi angle the wild-type loop requires. In a transmembrane helix this would break the helix outright; in this lumenal segment, the cost is a forced kink and the displacement of the immediately adjacent Arg805 — the polar/charged anchor that almost certainly contributes to the lumenal hydrogen-bond network around the ATF6-sensing face.
DynaMut2 reports DeltaDeltaG = +0.7 kcal/mol (labelled stabilising by the local energy function, which over-weights van der Waals packing gains from proline's rigid ring). The interpretation here is not that the fold is more stable globally — it is that the residue's new conformation is locally favorable while the protein's downstream geometry is forced off its native trajectory. AlphaMissense scores this 0.991 — about as high a pathogenicity score as the model produces, indicating that despite the mild DeltaDeltaG, the evolutionary signal at this position is unambiguous: A806 is conserved for a reason the energy function alone cannot see.
The Phe775-Phe810 aromatic contact within 4 Angstrom of A806 is the structural detail most likely affected. Two phenylalanines stacked at this distance constitute a pi-stacking interaction worth 2-4 kcal/mol on their own, and the proline-induced backbone kink almost certainly displaces one or both rings out of register. Combined with the loss of the Arg805 anchor, the consequence is a localized rearrangement of the ATF6-sensing face — a high-leverage mechanistic story that the gross stability number does not tell.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the A806P 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.