I489M

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Isoleucine → Methionine at position 489 · Connecting loop · WFS1 (Wolframin)

Ile→Met p489 loop AM=0.08 ddg=-0.49 pLDDT=79. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type I489 — hydrogen bond to V501

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DynaMut2 mutant · I489M

Mutant M489 — hydrophobic contact to V491 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N500	N500	Preserved
Hydrogen bond	V501	V501	Preserved
Polar contact	V501	V501	Preserved
Hydrophobic	V491	—	Lost
Hydrophobic	V501	V501	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

-0.49kcal/mol

Destabilising — mild

AlphaMissense

0.079

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 0.0030%

cDNA changec.1467C>G

ClinVar accessionVCV000449979

Last evaluated2025/09/26 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: THR490 (2.5 Å — partner of T490A), PHE488 (2.5 Å), VAL501 (4.4 Å). Same loop as T490A. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

methionine chemistry

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

Sister to T490A in same loop.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the I489M 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 I489M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin