D729N
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialAspartate → Asparagine at position 729 in lumenal domain. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.86.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R732 | — | Lost |
| Ionic bond | H763 | — | Lost |
| Hydrogen bond | F725 | F725 | Preserved |
| Hydrogen bond | R732 | R732 | Preserved |
| Hydrogen bond | C733 | C733 | Preserved |
| Hydrogen bond | H763 | H763 | Preserved |
| Polar contact | F725 | F725 | Preserved |
| Polar contact | — | I727 | Gained |
| Polar contact | M731 | — | Lost |
| Polar contact | R732 | R732 | Preserved |
| Polar contact | C733 | C733 | Preserved |
| Polar contact | H763 | H763 | Preserved |
| Van der Waals | M731 | — | Lost |
| Van der Waals | — | C733 | 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 for Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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 South Asian: AF 0.109% (99 of 91,068 alleles), 14.3x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 South Asian). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| South Asian | 0.109% | 99 / 91,068 | 1 | ~1 in 460 |
| African / African American | 0.013% | 10 / 75,064 | 0 | ~1 in 3750 |
| East Asian | 0.011% | 5 / 44,880 | 0 | ~1 in 4490 |
| Ashkenazi Jewish | 0.0068% | 2 / 29,594 | 0 | ~1 in 7400 |
| Remaining individuals | 0.0048% | 3 / 62,476 | 0 | ~1 in 10410 |
| European (non-Finnish) | 0.00034% | 4 / 1,179,924 | 0 | ~1 in 147490 |
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 729 in lumenal domain. Neighbors: TRP730 (2.5 Å), GLY728 (2.5 Å), PHE725 (3.8 Å). Near the L723P/P724S/P724L cluster.
D729N charge loss adjacent to L723-P724 loop variant cluster. |ΔΔG| 0.86; AM 0.12 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: charge loss near L723-P724 loop region. Therapeutic: site-directed at the 725-734 lumenal microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the D729N 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.