K876T
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialLysine → Threonine at position 876 inside TM11. ClinVar Conflicting including T2D. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.49.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | H872 | H872 | Preserved |
| Hydrogen bond | G873 | G873 | Preserved |
| Hydrogen bond | F879 | F879 | Preserved |
| Hydrogen bond | D880 | D880 | Preserved |
| Hydrogen bond | A889 | — | Lost |
| Hydrogen bond | A890 | — | Lost |
| Polar contact | H872 | H872 | Preserved |
| Polar contact | G873 | G873 | Preserved |
| Polar contact | A878 | — | Lost |
| Polar contact | F879 | F879 | Preserved |
| Polar contact | D880 | D880 | Preserved |
| Polar contact | A889 | — | Lost |
| Polar contact | A890 | — | Lost |
| Van der Waals | H872 | — | Lost |
| Van der Waals | A878 | — | Lost |
| Hydrophobic | A889 | A889 | 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 Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant). 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.
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, 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: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in African / African American: AF 0.174% (131 of 75,078 alleles), 19.8x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 African / African American). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| African / African American | 0.174% | 131 / 75,078 | 1 | ~1 in 290 |
| Remaining individuals | 0.0064% | 4 / 62,500 | 0 | ~1 in 7810 |
| Admixed American | 0.0050% | 3 / 60,032 | 0 | ~1 in 10010 |
| European (non-Finnish) | 0.00034% | 4 / 1,180,042 | 0 | ~1 in 147510 |
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 876 in TM11. Neighbors: PHE877 (2.4 Å), VAL875 (2.5 Å — partner of V875M), HIS872 (3.7 Å — same H872 in V871G cluster).
K876T joins the TM11 multi-variant cluster. The wild-type K876 likely serves as a 'positive-inside rule' anchor at the TM11 cytoplasmic end; losing it perturbs TM11 topology. AM 0.29 under-call; T2D does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: loss of positive-inside anchor at TM11. Therapeutic: TM11 multi-variant cluster (V871G/M, V875M, A874T, P885L).
Why this matters
Feed this card to Wolfram Intelligence
Download the K876T 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.