K705N
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialLysine → Asparagine at position 705 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.990 (near-maximum), DynaMut2 ΔΔG -0.66 kcal/mol (destabilising). A charge-loss variant in the high-confidence lumenal fold.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | D801 | — | Lost |
| Hydrogen bond | T778 | T778 | Preserved |
| Hydrogen bond | D801 | — | Lost |
| Hydrogen bond | — | Q819 | Gained |
| Polar contact | R703 | R703 | Preserved |
| Polar contact | T778 | T778 | Preserved |
| Polar contact | — | G780 | Gained |
| Polar contact | D801 | — | Lost |
| Polar contact | Q819 | Q819 | Preserved |
| Van der Waals | D801 | — | Lost |
| Van der Waals | — | Q819 | Gained |
| Hydrophobic | T778 | — | Lost |
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 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 705 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places K705 within 5 Å of TYR706 (2.4 Å), PHE704 (2.5 Å), THR778 (3.6 Å, a longer-range contact across the lumenal fold), GLN819 (4.4 Å, another distal contact), and ARG703 (4.5 Å). The neighbors are aromatic-rich (Y706, F704), polar (T778, Q819), and basic (R703, K705 itself).
The wild-type lysine at 705 carries a positive charge that likely participates in a salt-bridge or hydrogen-bonding network with the nearby threonine (T778) and glutamine (Q819) residues — both H-bond acceptors. The lysine side chain is long enough (4-carbon alkyl + amine) to reach across to these distal positions, contributing to a folded geometry that brings sequence-distant residues into proximity.
Replacing lysine with asparagine removes the positive charge and shortens the side chain. The polar amide of asparagine can still hydrogen-bond, but it can no longer reach the same distal positions as the lysine's longer chain. The local fold geometry that depends on the K705-T778 or K705-Q819 contact is perturbed.
DynaMut2's |ΔΔG| of 0.66 reflects the modest energetic cost of the fold rearrangement. AlphaMissense's 0.990 score captures the severity of the lost functional contact.
Druggability Assessment
The mechanism is loss of a long-range electrostatic/H-bond contact (K705 to T778 or Q819) that the wild-type residue's extended side chain made. Therapeutic strategy: site-directed small molecules that bridge the K705-T778-Q819 microregion, restoring the long-range contact the wild-type lysine provided.
This is a good example of how the Atlas's PDB neighbor analysis surfaces distal contacts that sequence-based analysis would miss. T778 is 73 residues away from K705 in sequence but only 3.6 Å away in structure.
Why this matters
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