A559D
Category 3/4 — Most DruggableLikely pathogenicCytoplasmic · predictedEditorialAlanine → Aspartate at position 559 in a connecting loop — sitting immediately adjacent to position 558, the location of the Atlas's flagship R558C variant (the most common WFS1 mutation in the Ashkenazi Jewish population). ClinVar Likely pathogenic. AlphaMissense 0.979, DynaMut2 ΔΔG -0.73 kcal/mol (destabilising). A position-adjacency variant with direct relevance to R558C.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | S430 | Gained |
| Hydrogen bond | — | E431 | Gained |
| Hydrogen bond | G555 | G555 | Preserved |
| Hydrogen bond | L556 | L556 | Preserved |
| Hydrogen bond | G562 | G562 | Preserved |
| Hydrogen bond | Y563 | Y563 | Preserved |
| Polar contact | S430 | S430 | Preserved |
| Polar contact | E431 | E431 | Preserved |
| Polar contact | — | V434 | Gained |
| Polar contact | G555 | G555 | Preserved |
| Polar contact | L556 | L556 | Preserved |
| Polar contact | L557 | L557 | Preserved |
| Polar contact | I561 | I561 | Preserved |
| Polar contact | G562 | G562 | Preserved |
| Polar contact | Y563 | Y563 | Preserved |
| Carbonyl | G562 | G562 | Preserved |
| Van der Waals | E431 | E431 | Preserved |
| Van der Waals | — | L556 | Gained |
| Van der Waals | G562 | G562 | Preserved |
| Hydrophobic | E431 | — | Lost |
| Hydrophobic | V434 | V434 | Preserved |
| Hydrophobic | Y563 | Y563 | 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 Likely 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 559 sits in a connecting loop. The AlphaFold model places A559 within 5 Å of SER560 (2.5 Å), ARG558 (2.5 Å — the residue mutated in R558C, the Atlas flagship variant), GLU431 (3.2 Å), GLY555 (3.7 Å), LEU556 (3.8 Å), and GLY562 (4.4 Å). The proximity to R558 is the most structurally consequential observation: A559 is the immediate sequence neighbor of the Ashkenazi-population variant, and they share a microenvironment in the loop.
The wild-type alanine at 559 contributes minimal side-chain mass and no functional groups. It serves primarily as a steric and conformational spacer between R558 and the rest of the loop. Critically, the wild-type R558 makes ionic contacts with E431 (3.2 Å from A559, suggesting the loop region wraps around an E431 anchor point) — the same kind of contact disrupted in the R558C variant.
Replacing alanine with aspartate at 559 introduces a negatively-charged carboxylate into the loop one residue away from R558. In the wild-type, R558 is positively charged and E431 is negatively charged, and they form a salt bridge. Adding a second negative charge at position 559, immediately adjacent to R558, perturbs this salt-bridge geometry — the new D559 carboxylate competes with E431 for the R558 guanidinium's electrostatic interaction.
DynaMut2 returns |ΔΔG| of 0.73 kcal/mol — the fold survives, but the loop electrostatic network is materially perturbed. AlphaMissense's 0.979 score reflects the high pathogenic potential of disrupting the same salt bridge geometry that R558C also disrupts (from the R558 side rather than the partner side).
Druggability Assessment
The mechanism is disruption of the R558-E431 salt bridge through an adjacent introduced charge — the same therapeutic surface targeted by R558C. A drug designed to rescue the R558C variant by re-stabilizing the loop's electrostatic network would, in principle, also rescue A559D.
This is the Atlas's clearest demonstration of a 'sister-variant' relationship: two distinct pathogenic substitutions perturbing the same structural feature from different angles. Drug discovery at the R558-E431-A559 microregion has two converging targets.
Why this matters
Feed this card to Wolfram Intelligence
Download the A559D 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.