A671S

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

Alanine → Serine at position 671 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Ala→Ser p671 lumenal AM=0.06 ddg=+0.05 pLDDT=85. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type A671 — hydrogen bond to Q667

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DynaMut2 mutant · A671S

Mutant S671 — hydrogen bond contact to Q668 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q667	Q667	Preserved
Hydrogen bond	Q668	—	Lost
Hydrogen bond	A677	A677	Preserved
Polar contact	Q667	Q667	Preserved
Polar contact	Q668	Q668	Preserved
Polar contact	Y669	Y669	Preserved
Polar contact	—	A677	Gained
Van der Waals	Y669	Y669	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

0.05kcal/mol

Stabilising — mild

AlphaMissense

0.061

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 0.0014%

cDNA changec.2011G>T

ClinVar accessionVCV000905057

Last evaluated2024/03/28 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: GLY670 (2.5 Å — same G670 in G674 cluster!), LEU672 (2.5 Å — L672P!), GLN667 (3.8 Å — same Q667 as Y669 cluster!). Adjacent to G674 + Y669 hubs. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

polarity introduced

Position in the protein

C-terminal lumenal domain

Druggability Assessment

Cat 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 G674 + Y669 hubs.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A671S 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 A671S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal