V871G

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

Valine → Glycine at position 871 · TM11 (870-890), helical transmembrane · WFS1 (Wolframin)

Valine → Glycine at position 871 inside TM11. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.27 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.76.

Interactive 3D Structure

Wild-type reference

Wild-type V871 — hydrogen bond to V875

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DynaMut2 mutant · V871G

Mutant G871 — hydrogen bond to W867 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	W867	W867	Preserved
Hydrogen bond	A874	A874	Preserved
Hydrogen bond	V875	V875	Preserved
Polar contact	W867	W867	Preserved
Polar contact	—	R868	Gained
Polar contact	G873	—	Lost
Polar contact	A874	A874	Preserved
Polar contact	V875	V875	Preserved
Van der Waals	W867	—	Lost
Van der Waals	G873	—	Lost
Van der Waals	A874	—	Lost
Van der Waals	—	V875	Gained
Hydrophobic	V875	—	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

DynaMut2 ΔΔG

-0.76kcal/mol

Destabilising — mild

AlphaMissense

0.268

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 conditionsCataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceAD: Cataract + DFNA6.

Population frequency (gnomAD v4)Low frequency · AF 0.010%

cDNA changec.2612T>G

ClinVar accessionVCV001572110

Last evaluated2025/09/28 00:00

Observed in the general population.

Structural Context

Position 871 at TM11 start. Neighbors: HIS872 (2.5 Å — same H872 as K876T/A874T), THR870 (2.5 Å), TRP867 (3.7 Å — aromatic). The H872-V871-T870-W867 region is the TM11 start.

V871G removes side chain creating cavity in TM11 hydrophobic core. |ΔΔG| 0.76 + AM 0.27 under-call + multi-phenotype confirm pathogenicity.

Amino-acid chemistry

Valine (V) → Glycine (G) — branched aliphatic replaced by smallest amino acid. Massive cavity creation.

Position in the protein

TM11 (residues 870–890) · position 871 at TM11 start (pLDDT 74).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.76. AlphaMissense 0.27 below threshold but multi-phenotype confirms pathogenicity.

Mechanism: cavity creation at TM11 start. Therapeutic: TM11 multi-variant cluster.

Why this matters

V871G + V871M at same position. TM11 cluster expands further.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V871G 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 V871G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane870–890 · Helical

Natural variant871–871 · in dbSNP:rs71532874