G553S

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Glycine → Serine at position 553 · Connecting loop · WFS1 (Wolframin)

Gly→Ser p553 loop AM=0.08 ddg=-0.06 pLDDT=81. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type G553 — hydrogen bond to L557

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DynaMut2 mutant · G553S

Mutant S553 — energy-minimized; 1 new contact formed

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L556	L556	Preserved
Hydrogen bond	L557	L557	Preserved
Polar contact	L556	L556	Preserved
Polar contact	L557	L557	Preserved
Van der Waals	—	L557	Gained

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

-0.06kcal/mol

Destabilising — mild

AlphaMissense

0.076

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 conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0086%

cDNA changec.1657G>A

ClinVar accessionVCV000215359

Last evaluated2025/10/16 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: THR552 (2.5 Å), LEU554 (2.5 Å — same L554 as R558C neighborhood!), LEU556 (4.4 Å). Same loop as R558C — Ashkenazi flagship region. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

glycine flexibility lost

Position in the protein

Connecting loop

Druggability Assessment

Cat 3/4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

Adjacent to R558C Ashkenazi flagship loop.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the G553S 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 G553S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin