G576S

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Glycine → Serine at position 576 · TM8 (563-583), helical transmembrane · WFS1 (Wolframin)

Glycine → Serine at position 576 inside TM8. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.46.

Interactive 3D Structure

Wild-type reference

Wild-type G576 — hydrogen bond to I572

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DynaMut2 mutant · G576S

Mutant S576 — polar contact contact to V574 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I572	I572	Preserved
Hydrogen bond	L579	L579	Preserved
Hydrogen bond	V580	V580	Preserved
Polar contact	I572	I572	Preserved
Polar contact	L573	L573	Preserved
Polar contact	V574	—	Lost
Polar contact	L579	L579	Preserved
Polar contact	V580	V580	Preserved
Van der Waals	—	A578	Gained
Van der Waals	V580	V580	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

-0.46kcal/mol

Destabilising — mild

AlphaMissense

0.145

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 conditionsMonogenic diabetes; WFS1-Related Spectrum Disorders

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Low frequency · AF 0.462%

cDNA changec.1726G>A

ClinVar accessionVCV000045439

Last evaluated2026/02/02 00:00

Observed in the general population.

Structural Context

Position 576 in TM8. Neighbors: LEU577 (2.5 Å), ALA575 (2.5 Å — A575G partner!), ILE572 (3.5 Å). The 575-576 region — A575G + G576S adjacent.

G576S removes glycine flexibility + adds polarity to TM8 bilayer environment. AM 0.15 under-call; multi-phenotype confirms.

Amino-acid chemistry

Glycine (G) → Serine (S) — smallest replaced by polar hydroxyl.

Position in the protein

TM8 (residues 563–583) · position 576 (pLDDT 84).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.46. AlphaMissense 0.15 below threshold but multi-phenotype confirms.

Mechanism: glycine removal + polarity in TM8. Therapeutic: same 575-576 region as A575G.

Why this matters

G576S + A575G — adjacent TM8 variants both pathogenic.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the G576S 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 G576S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane563–583 · Helical

Natural variant576–576 · in dbSNP:rs1805069