D171N
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialAspartate → Asparagine at position 171 in N-terminal cytoplasmic domain. ClinVar Conflicting. AlphaMissense 0.20 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.08 (neutral).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R174 | — | Lost |
| Hydrogen bond | R174 | R174 | Preserved |
| Hydrogen bond | A175 | A175 | Preserved |
| Polar contact | R174 | R174 | Preserved |
| Polar contact | A175 | A175 | Preserved |
| Van der Waals | — | A175 | Gained |
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 Finnish: AF 0.040% (25 of 63,184 alleles), 9.1x 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. |
|---|---|---|---|---|
| Finnish | 0.040% | 25 / 63,184 | 0 | ~1 in 1260 |
| Admixed American | 0.032% | 19 / 60,018 | 0 | ~1 in 1580 |
| South Asian | 0.0044% | 4 / 91,040 | 0 | ~1 in 11380 |
| Remaining individuals | 0.0032% | 2 / 62,504 | 0 | ~1 in 15630 |
| European (non-Finnish) | 0.0017% | 20 / 1,180,014 | 0 | ~1 in 29500 |
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 171 in cytoplasmic domain. Neighbors: THR170 (2.5 Å), LEU172 (2.5 Å), ARG174 (3.8 Å — R174 partner of R177C cluster region). The R174-D171 likely salt bridge.
D171N eliminates negative charge while preserving amide H-bond. R174 loses salt-bridge partner. ΔΔG ≈ 0; AM 0.20 under-call. ClinVar Conflicting with low evidence.
Druggability Assessment
Mechanism: loss of D171-R174 salt bridge. Therapeutic: same R174/R177 cluster microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the D171N 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.