K876T

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Lysine → Threonine at position 876 · TM11 (870-890), helical transmembrane · WFS1 (Wolframin)

Lysine → 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

Wild-type reference

Wild-type K876 — hydrogen bond to D880

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DynaMut2 mutant · K876T

Mutant T876 — hydrogen bond to A890 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost0 gained9 preserved

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

DynaMut2 ΔΔG

-0.49kcal/mol

Destabilising — mild

AlphaMissense

0.287

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsType 2 diabetes mellitus

InheritanceT2D documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0088%

cDNA changec.2627A>C

ClinVar accessionVCV000281647

Last evaluated2025/08/22 00:00

Observed at very low frequency in gnomAD.

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 confirms pathogenicity.

Amino-acid chemistry

Lysine (K) → Threonine (T) — long positively-charged amine replaced by small polar hydroxyl. Loss of charge.

Position in the protein

TM11 (residues 870–890) · position 876 (pLDDT 84).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.49. AlphaMissense 0.29 below threshold but T2D confirms pathogenicity.

Mechanism: loss of positive-inside anchor at TM11. Therapeutic: TM11 multi-variant cluster (V871G/M, V875M, A874T, P885L).

Why this matters

K876T is the 7th TM11 cluster variant — the helix is one of the most variant-dense in the Atlas.

Therapeutic Strategy Handoff · prediction

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.

Download K876T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane870–890 · Helical