A684T
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialAlanine → Threonine at position 684 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.952, DynaMut2 ΔΔG +0.11 kcal/mol — essentially neutral (slightly stabilising). A polar-introduction variant adjacent to the R685 position (R685P atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Van der Waals | N682 | N682 | Preserved |
| Van der Waals | I688 | I688 | 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 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.
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. |
|---|---|---|---|---|
| Admixed American · under-sampled | 0.0065% | 1 / 15,292 | 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 684 sits in wolframin's C-terminal lumenal domain, immediately preceding R685. The AlphaFold model places A684 within 5 Å of MET683 (2.5 Å), ARG685 (2.5 Å — the partner residue in R685P atlas card), GLN687 (4.0 Å), ASN682 (4.0 Å), and THR686 (4.4 Å). The local environment is heavy on polar and basic residues (R685, Q687, N682, T686).
The wild-type alanine at 684 provides minimal side-chain volume and no functional groups — it serves as a steric placeholder between M683 and R685. Replacing it with threonine introduces a polar hydroxyl group into a polar-rich environment. The hydroxyl could either form a new hydrogen bond with R685, T686, N682, or Q687, or perturb the existing H-bond network among those residues.
The ΔΔG of +0.11 indicates near-neutral structural impact — the new H-bonding option roughly compensates for any local strain. But AlphaMissense's 0.952 score plus the ClinVar Pathogenic classification confirm pathogenic mechanism.
The mechanism is most plausibly disruption of the R685 H-bond network. The wild-type A684 placeholder allows R685 to project its side chain in a specific direction; the introduced T684 hydroxyl competes for R685's H-bonding attention and pulls it out of its functional orientation. Combined with the R685P atlas card (same R685 environment disrupted from the other side), this microregion has two convergent therapeutic targets.
Druggability Assessment
The mechanism is introduction of a new H-bond donor that captures or redirects R685's functional H-bonding, disrupting the partner-recognition surface R685 normally provides. Drug discovery targets the R685 microregion — same target as R685P, approached from a different angle.
Two Atlas variants in the same 683-687 region converge on a single therapeutic geometry: a small molecule that stabilizes the wild-type R685 orientation.
Why this matters
Feed this card to Wolfram Intelligence
Download the A684T 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.