D118A
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialAspartate → Alanine at position 118 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.35 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L121 | — | Lost |
| Hydrogen bond | N122 | N122 | Preserved |
| Polar contact | E120 | E120 | Preserved |
| Polar contact | L121 | L121 | Preserved |
| Polar contact | N122 | N122 | Preserved |
| Van der Waals | E120 | — | Lost |
| Hydrophobic | L121 | L121 | 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes
- 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 African / African American: AF 0.902% (676 of 74,986 alleles), 18.3x 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. |
|---|---|---|---|---|
| African / African American | 0.902% | 676 / 74,986 | 0 | ~1 in 55 |
| Remaining individuals | 0.077% | 48 / 62,316 | 0 | ~1 in 650 |
| Middle Eastern | 0.066% | 4 / 6,056 | 0 | ~1 in 760 |
| Admixed American | 0.056% | 33 / 59,350 | 0 | ~1 in 900 |
| European (non-Finnish) | 0.0027% | 32 / 1,177,644 | 0 | ~1 in 18400 |
| South Asian · under-sampled | 0.0011% | 1 / 89,444 | 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 118 sits in wolframin's N-terminal cytoplasmic domain. Neighbors: GLU119 (2.5 Å — adjacent existing glutamate), THR117 (2.5 Å), ASN122 (4.4 Å). The wild-type D118 + adjacent E119 form a charged surface patch in the cytoplasmic domain — likely a recognition surface for partner proteins.
Replacing D118 with alanine eliminates one of two negative charges from this patch. The local electrostatic surface is reduced; the partner-recognition geometry that depended on the D118-E119 double-negative signature is perturbed.
The |ΔΔG| of 0.14 is small — the fold absorbs the substitution. AlphaMissense's 0.35 is below threshold (AM under-call). Monogenic diabetes clinical evidence does not resolve pathogenicity (ClinVar: conflicting submissions) through cytoplasmic partner-recognition disruption.
Druggability Assessment
Mechanism: charge loss from D118-E119 cytoplasmic surface patch. Therapeutic strategy: site-directed at the cytoplasmic recognition surface.
Why this matters
Feed this card to Wolfram Intelligence
Download the D118A 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.