I561V

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Isoleucine → Valine at position 561 · Connecting loop · WFS1 (Wolframin)

Ile→Val p561 loop AM=0.06 ddg=-0.25 pLDDT=85. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type I561 — hydrogen bond to L565

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DynaMut2 mutant · I561V

Mutant V561 — polar contact contact to L557 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L557	L557	Preserved
Hydrogen bond	L565	L565	Preserved
Polar contact	L557	L557	Preserved
Polar contact	A559	A559	Preserved
Polar contact	F564	—	Lost
Polar contact	L565	L565	Preserved
Van der Waals	L557	L557	Preserved
Hydrophobic	L557	L557	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

-0.25kcal/mol

Destabilising — mild

AlphaMissense

0.055

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 0.0022%

cDNA changec.1681A>G

ClinVar accessionVCV001320392

Last evaluated2026/01/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: GLY562 (2.5 Å — G562 in A559D region!), SER560 (2.5 Å — same S560 as A559D!), LEU557 (3.7 Å — L557 in R558C loop!). Same R558C connecting loop. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

conservative volume reduction

Position in the protein

Connecting loop

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

R558C connecting loop variant.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the I561V 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 I561V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin