D771Y
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAspartate → Tyrosine at position 771. ClinVar Conflicting. AlphaMissense 0.855, ΔΔG +0.18. Third variant at position 771 — same as D771H plus the N714 network position.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | I712 | Gained |
| Hydrogen bond | N714 | — | Lost |
| Hydrogen bond | K768 | K768 | Preserved |
| Hydrogen bond | Y773 | Y773 | Preserved |
| Polar contact | N714 | — | Lost |
| Polar contact | K768 | K768 | Preserved |
| Polar contact | Y773 | Y773 | Preserved |
| Aromatic / π | — | Y773 | Gained |
| Van der Waals | — | N714 | Gained |
| Van der Waals | K768 | K768 | Preserved |
| Van der Waals | Y773 | — | Lost |
| Hydrophobic | I712 | I712 | Preserved |
| Hydrophobic | — | N714 | Gained |
| Hydrophobic | — | K768 | Gained |
| 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
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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.0015% | 1 / 68,044 | 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 771 same neighbors as D771H: ARG772 (2.4 Å — salt-bridge partner), PHE770 (2.5 Å), LYS768 (3.8 Å), ASP713 (3.8 Å — same D713 in the N714 polar network).
D771Y is the second pathogenic substitution at position 771 (with D771H). Where D771H reversed charge and added aromatic, D771Y eliminates charge entirely and adds aromatic volume. The R772 salt-bridge is broken; the F770 aromatic now has a tyrosine neighbor creating a tandem aromatic.
ΔΔG essentially neutral; AM 0.855 confirms severe consequence.
Druggability Assessment
Mechanism: loss of D771-R772 salt bridge + tandem aromatic formation. Therapeutic: same D771 microregion as D771H, N714T/S/K.
Why this matters
Feed this card to Wolfram Intelligence
Download the D771Y 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.