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T490A

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial
ThreonineAlanine at position 490 · Connecting loop · WFS1 (Wolframin)

Thr→Ala p490 loop AM=0.08 ddg=-0.34 pLDDT=81. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference
Wild-type T490 — hydrogen bond to N500
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DynaMut2 mutant · T490A
Mutant A490 — hydrogen bond to N500 lost (4 contacts lost)
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Bond changes · DynaMut2 interaction analysis

4 lost1 gained2 preserved
Interaction typeWild-type partnerMutant partnerStatus
Hydrogen bondL499L499Preserved
Hydrogen bondN500Lost
Polar contactL499L499Preserved
Polar contactN500Lost
CarbonylL499Lost
Van der WaalsN500Lost
HydrophobicV498Gained

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
-0.34kcal/mol
Destabilising — mild
AlphaMissense
0.082
LBen
AlphaFold pLDDT
81
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 0.00021%
cDNA changec.1468A>G
ClinVar accessionVCV000505052
Last evaluated2016/06/02 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: VAL491 (2.5 Å), ILE489 (2.5 Å — I489M!), LEU499 (3.5 Å — L499F partner!). Multi-variant target. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry
H-bond loss + side-chain reduction
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

T490A + I489M + L499F cluster.
Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T490A 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 T490A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1890 · Wolframin