A806P

Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorial

Alanine → Proline at position 806 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Proline 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

Wild-type reference

Wild-type A806 — hydrogen bond to F775

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DynaMut2 mutant · A806P

Mutant P806 — hydrogen bond contact to K774 lost

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Bond changes · DynaMut2 interaction analysis

1 lost4 gained7 preserved

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

DynaMut2 ΔΔG

0.70kcal/mol

Stabilising — mild

AlphaMissense

0.991

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1; WFS1-Related Spectrum Disorders

InheritanceAutosomal dominant and autosomal recessive forms both reported.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00034%

cDNA changec.2416G>C

ClinVar accessionVCV001073764

Last evaluated2023/07/31 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Alanine (small, hydrophobic, unrestricted backbone phi/psi) to Proline (cyclic side chain, locks phi near -60 degrees, eliminates the backbone amide NH as a hydrogen-bond donor) at position 806.

Position in the protein

Position 806 sits deep in wolframin's largest soluble module — the C-terminal lumenal domain (residues 653-869) that faces the ER lumen and houses the ATF6-binding interface, the Na+/K+ ATPase beta1 contact, and the calcium-sensing apparatus. pLDDT 90.88 places the residue inside a confidently modeled, well-ordered region.

Druggability Assessment

Final classification: Category 4 — Stable Fold, Function Disrupted. The convergent evidence reads cleanly: pLDDT 90.88 places A806 inside an ordered, modelable region (no IDR exclusion); DeltaDeltaG magnitude of 0.7 kcal/mol means the fold survives the substitution — this is not gross misfolding requiring gene replacement; AlphaMissense 0.991 confirms the position is functionally constrained despite mild energetic cost; and the lumenal location places the perturbation directly on the ATF6-sensing face, the most therapeutically interesting surface in wolframin. The lost contact set is specific and small. A pharmacological chaperone or site-directed small molecule that restores the Phe775-Phe810 aromatic register, or that compensates for the Arg805 displacement, becomes the obvious next experiment. The fold is intact; the lesion is local; the surface is accessible from the lumen. Gene therapy is not warranted at this magnitude — this is exactly the bucket where the Atlas thesis predicts small-molecule rescue should outperform AAV.

Why this matters

A806P is one of the cleanest illustrations of why DeltaDeltaG alone is not enough. A naive read of the stability number (mildly stabilising) would put this variant in a low-priority bin; the AlphaMissense score and the structural specifics tell the opposite story. The Atlas's value here is precisely that it forces the reader to look at the residue's neighbors, the backbone constraint, and the functional surface — not just the energy. For the wolframin program, A806P is a candidate proof point for the pharmacological-chaperone hypothesis. If a CFTR-corrector-style molecule can stabilize the native lumenal geometry around the Phe775-Phe810 stack, the same chemistry should transfer to other lumenal Category 4 variants in this neighborhood. That makes A806P a structural anchor for downstream screening work, not just a single clinical case.

Therapeutic Strategy Handoff · prediction

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.

Download A806P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal