K634T
Category 3/4 — Most DruggablePathogenicTransmembrane · predictedEditorialLysine → Threonine at position 634 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic, associated with DFNA6 hearing loss. AlphaMissense 0.883, DynaMut2 ΔΔG -0.32 kcal/mol (destabilising). A charge-loss variant in a TM helix.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E403 | — | Lost |
| Hydrogen bond | E403 | — | Lost |
| Hydrogen bond | S630 | S630 | Preserved |
| Hydrogen bond | S631 | S631 | Preserved |
| Hydrogen bond | V638 | V638 | Preserved |
| Polar contact | E403 | — | Lost |
| Polar contact | S630 | S630 | Preserved |
| Polar contact | S631 | S631 | Preserved |
| Polar contact | M632 | M632 | Preserved |
| Polar contact | L637 | L637 | Preserved |
| Polar contact | V638 | V638 | Preserved |
| Van der Waals | S630 | S630 | Preserved |
| Van der Waals | M632 | M632 | 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
- 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 Pathogenic for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). 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.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- 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. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,112,010 | 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 634 sits at the start of TM10. The AlphaFold model places K634 within 5 Å of LEU635 (2.5 Å), VAL633 (2.5 Å), SER631 (3.8 Å), SER630 (4.0 Å), and MET632 (4.3 Å). The local environment is hydrophobic-rich with two nearby serines (S630, S631) — characteristic of a TM-helix start in the lipid headgroup region.
The wild-type lysine at 634 is positioned where its long alkyl chain can extend toward the membrane-water interface and its primary amine can engage phospholipid headgroups. This is a 'positive-inside rule' position — basic residues at the cytoplasmic end of TM helices are stabilizing for membrane orientation.
Replacing lysine with threonine removes this positive-inside anchor. The new T634 is small and polar but cannot reach the membrane interface or engage headgroups. TM10's orientation may shift slightly to compensate.
The |ΔΔG| of 0.32 reflects modest structural cost. AlphaMissense's 0.883 score plus the DFNA6 clinical association confirm pathogenic consequence — likely from altered TM10 topology and downstream effects on helix-helix packing (notably the TM3-TM10 interface that T641K disrupts).
Druggability Assessment
The mechanism is loss of the positive-inside anchor at the TM10 cytoplasmic end, with secondary effect on TM10's overall topology and TM3-TM10 packing. Therapeutic strategy: site-directed at the TM10 N-terminal membrane interface.
Combined with T641K (Atlas card adjacent — TM10 mid-helix with TM3-TM10 interface mechanism), drug discovery targeting TM10 has two convergent variant targets.
Why this matters
Feed this card to Wolfram Intelligence
Download the K634T 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.