K363T
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialLysine → Threonine at position 363 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.874, DynaMut2 ΔΔG -0.43 kcal/mol (destabilising). Charge-loss variant adjacent to T361 (T361I Atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I359 | I359 | Preserved |
| Hydrogen bond | C360 | C360 | Preserved |
| Hydrogen bond | Q366 | Q366 | Preserved |
| Hydrogen bond | D367 | D367 | Preserved |
| Hydrogen bond | — | P404 | Gained |
| Hydrogen bond | S630 | — | Lost |
| Polar contact | I359 | I359 | Preserved |
| Polar contact | C360 | C360 | Preserved |
| Polar contact | T361 | T361 | Preserved |
| Polar contact | F365 | F365 | Preserved |
| Polar contact | Q366 | Q366 | Preserved |
| Polar contact | D367 | D367 | Preserved |
| Polar contact | S630 | — | Lost |
| Van der Waals | — | I359 | Gained |
| Van der Waals | — | T361 | Gained |
| Van der Waals | F365 | F365 | Preserved |
| Van der Waals | D367 | — | Lost |
| Van der Waals | S630 | — | Lost |
| Hydrophobic | P404 | — | 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- No assertion criteria were provided (0★). Treat the conditions above as unverified submissions, 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: 0★ no assertion criteria provided. 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. |
|---|---|---|---|---|
| African / African American · under-sampled | 0.0024% | 1 / 41,348 | 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 363 sits in a connecting loop, two residues from T361 (T361I Atlas card). The AlphaFold model places K363 within 5 Å of LEU362 (2.5 Å), VAL364 (2.5 Å), CYS360 (3.6 Å), ILE359 (3.8 Å), and GLN366 (4.2 Å).
The wild-type lysine at 363 is the partner residue identified in the T361I Atlas card — T361's hydroxyl was hypothesized to H-bond with K363's amine. K363T replaces lysine with threonine, which is precisely the residue that T361I introduced at the wild-type T position. The K363 amine is replaced by a hydroxyl.
This means K363T and T361I together replace the wild-type T361-K363 H-bond pair (hydroxyl-amine) with a T361-T363 pair (hydroxyl-hydroxyl in the T361 variant; or the wild-type T plus T363 in the K363T variant). The geometry changes but H-bonding may persist.
The |ΔΔG| of 0.43 reflects modest fold cost. AlphaMissense's 0.874 + Wolfram 1 confirm severe functional consequence — the partner-recognition geometry depends on the precise wild-type chemistry, not just the H-bonding capacity.
Druggability Assessment
Mechanism is disruption of the T361-K363 H-bond pair. Therapeutic strategy: same microregion as T361I.
Why this matters
Feed this card to Wolfram Intelligence
Download the K363T 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.