T361S

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Threonine → Serine at position 361 · Connecting loop · WFS1 (Wolframin)

Threonine → Serine at position 361 in a connecting loop. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.756, ΔΔG +0.03 (neutral). Same position as T361I (Atlas flagship pathogenic-stabilising card).

Interactive 3D Structure

Wild-type reference

Wild-type T361 — hydrogen bond to F365

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DynaMut2 mutant · T361S

Mutant S361 — hydrogen bond to V358 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost3 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M357	M357	Preserved
Hydrogen bond	V358	V358	Preserved
Hydrogen bond	V364	V364	Preserved
Hydrogen bond	F365	F365	Preserved
Hydrogen bond	—	W540	Gained
Polar contact	M357	M357	Preserved
Polar contact	V358	V358	Preserved
Polar contact	I359	I359	Preserved
Polar contact	K363	K363	Preserved
Polar contact	V364	V364	Preserved
Polar contact	F365	F365	Preserved
Polar contact	—	W540	Gained
Van der Waals	M357	—	Lost
Van der Waals	I359	I359	Preserved
Van der Waals	—	K363	Gained
Hydrophobic	F408	—	Lost
Hydrophobic	V536	—	Lost
Hydrophobic	W540	—	Lost

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

0.03kcal/mol

Stabilising — mild

AlphaMissense

0.756

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram-like syndrome; Wolfram syndrome 1

InheritanceAD and AR documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1082C>G

ClinVar accessionVCV001486730

Last evaluated2024/10/25 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 361 same neighbors as T361I: LEU362 (2.5 Å), CYS360 (2.5 Å), VAL358 (3.8 Å), MET357 (3.9 Å).

T361S is the most conservative substitution possible at position 361 — preserving the H-bonding hydroxyl while only removing the methyl group. ΔΔG essentially neutral. Yet AlphaMissense 0.756 + Wolfram + Wolfram-like confirm pathogenicity.

Mechanism is the same as T361I (Atlas card): functional disruption rather than fold disruption. The K363 H-bond partner geometry is fine-tuned by the wild-type threonine's specific methyl positioning that serine cannot replicate.

Amino-acid chemistry

Threonine (T) → Serine (S) — small polar hydroxyl with methyl replaced by small polar hydroxyl without methyl. Conservative.

Position in the protein

Connecting loop · position 361 (pLDDT 91). Same as T361I.

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG ≈ 0. AlphaMissense 0.756 + multi-syndrome confirm severe consequence.

Mechanism: fine-grained geometry disruption at the T361-K363 H-bond pair. Therapeutic: same target as T361I.

Why this matters

T361S + T361I at same position — both pathogenic by functional mechanism. Position 361 demonstrates that even the most conservative T→S substitution breaks function.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T361S 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 T361S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin