T527I

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Threonine → Isoleucine at position 527 · Connecting loop · WFS1 (Wolframin)

Threonine → Isoleucine at position 527 in connecting loop. ClinVar Conflicting including WFS1-related + DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.53.

Interactive 3D Structure

Wild-type reference

Wild-type T527 — hydrogen bond to F524

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DynaMut2 mutant · T527I

Mutant I527 — hydrogen bond contact to F524 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F524	F524	Preserved
Hydrogen bond	L531	L531	Preserved
Hydrogen bond	V532	V532	Preserved
Polar contact	F524	F524	Preserved
Polar contact	K525	K525	Preserved
Polar contact	L531	L531	Preserved
Polar contact	V532	V532	Preserved
Van der Waals	—	F524	Gained
Van der Waals	K525	—	Lost
Van der Waals	L531	L531	Preserved
Hydrophobic	A519	A519	Preserved
Hydrophobic	—	L531	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

-0.53kcal/mol

Destabilising — mild

AlphaMissense

0.119

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 conditionsWFS1-related disorder; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMulti-phenotype AD.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0063%

cDNA changec.1580C>T

ClinVar accessionVCV000907533

Last evaluated2025/09/27 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 527 in connecting loop near TM7 start (TM7 = 529-549). Neighbors: TYR528 (2.5 Å), GLY526 (2.5 Å), LEU531 (3.9 Å — same L531 in L543P TM7 region).

T527I T→I substitution at the loop-TM7 boundary. AM 0.12 under-call; multi-phenotype confirms.

Amino-acid chemistry

Threonine (T) → Isoleucine (I) — polar hydroxyl replaced by branched aliphatic. Loss of H-bonding.

Position in the protein

Connecting loop · position 527 (pLDDT 78).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.53. AlphaMissense 0.12 below threshold but multi-phenotype confirms.

Mechanism: T→I lost H-bonding at TM7 boundary. Therapeutic: loop-TM7 boundary microregion.

Why this matters

T527I continues T→I class (with T337I, T361I, T361S, T461I).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T527I 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 T527I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin