D771H
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialAspartate → Histidine at position 771 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.857, DynaMut2 ΔΔG -0.34 kcal/mol (destabilising). A charge-sign-change-plus-aromatic variant in a polar network position.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | — | E717 | Gained |
| Hydrogen bond | — | I712 | Gained |
| Hydrogen bond | N714 | N714 | Preserved |
| Hydrogen bond | K768 | K768 | Preserved |
| Hydrogen bond | Y773 | — | Lost |
| Polar contact | — | I712 | Gained |
| Polar contact | N714 | N714 | Preserved |
| Polar contact | K768 | K768 | Preserved |
| Polar contact | Y773 | Y773 | Preserved |
| Aromatic / π | — | Y773 | Gained |
| Van der Waals | — | N714 | Gained |
| Van der Waals | K768 | — | Lost |
| Van der Waals | Y773 | Y773 | Preserved |
| Hydrophobic | I712 | I712 | Preserved |
| Hydrophobic | Y773 | Y773 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as 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: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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 771 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places D771 within 5 Å of ARG772 (2.4 Å — likely salt-bridge partner), PHE770 (2.5 Å), LYS768 (3.8 Å), ASP713 (3.8 Å — same residue cluster as N714T atlas card), and ASN714 (4.2 Å — direct N714 contact). The wild-type aspartate likely forms a salt bridge with R772 and contributes to the polar network involving N714 across the fold.
Replacing aspartate with histidine reverses the charge character: the lost negative charge eliminates the salt bridge with R772, and the introduced imidazole — neutral or protonated depending on local pH — cannot maintain the same electrostatic contribution. The ER lumen's mild acidity favors protonated histidine (positively charged), which would now repel R772 rather than attract it.
The N714 contact (4.2 Å) is the second key disruption: D771 and N714 are spatially close and likely form an H-bond. The new H771 is also a potential H-bonder but with different geometry; the network shifts.
The |ΔΔG| of 0.34 indicates fold absorbs the substitution. AlphaMissense's 0.857 score captures functional consequence — the disrupted R772 salt bridge and the perturbed N714 contact together signal severe pathogenic mechanism.
Druggability Assessment
The mechanism is loss of the D771-R772 salt bridge plus perturbation of the D771-N714 H-bond contact. Therapeutic strategy: site-directed at the D771-R772-N714 network. Combined with N714T (same network from the other side, atlas card adjacent), drug discovery has two convergent targets in this microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the D771H 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.