S308C

Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorial

Serine → Cysteine at position 308 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Serine → Cysteine at position 308 in N-terminal cytoplasmic domain. ClinVar Conflicting including congenital bilateral perisylvian syndrome. AlphaMissense 0.642, ΔΔG -0.01 (neutral). pLDDT 61 borderline.

Interactive 3D Structure

Wild-type reference

Wild-type S308 — hydrogen bond to I304

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DynaMut2 mutant · S308C

Mutant C308 — hydrogen bond to D305 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost4 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I304	I304	Preserved
Hydrogen bond	D305	D305	Preserved
Hydrogen bond	M312	M312	Preserved
Polar contact	I304	I304	Preserved
Polar contact	D305	—	Lost
Polar contact	—	A310	Gained
Polar contact	—	G311	Gained
Polar contact	M312	M312	Preserved
Polar contact	—	W613	Gained
Van der Waals	W613	—	Lost
Hydrophobic	—	W613	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

-0.01kcal/mol

Destabilising — mild

AlphaMissense

0.642

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 conditionsCongenital bilateral perisylvian syndrome

InheritanceCongenital bilateral perisylvian syndrome documented.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.923C>G

ClinVar accessionVCV001496445

Last evaluated2025/07/27 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

Position 308 near TM1 boundary. Neighbors: ARG309 (2.5 Å — same R309 as H313Y region), ALA307 (2.5 Å), ILE304 (3.8 Å), ASP305 (4.1 Å).

Replacing S308 with cysteine swaps hydroxyl for thiol. In the cytosol, the new C308 thiol is less reactive than in the ER lumen, but free cysteines in cytosol can still participate in glutathionylation or other regulatory thiol chemistry. ΔΔG essentially neutral; AM 0.642 + congenital syndrome confirm severe consequence.

Amino-acid chemistry

Serine (S) → Cysteine (C) — small polar hydroxyl replaced by small thiol. Both small; chemistry shifts from OH to SH.

Position in the protein

N-terminal cytoplasmic domain · position 308 (pLDDT 61 borderline). Near the TM1 boundary.

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG ≈ 0. AlphaMissense 0.642 + congenital syndrome confirm severe consequence.

Mechanism: hydroxyl-to-thiol substitution near R309. Therapeutic: site-directed at the cytoplasmic-TM1 boundary region.

Why this matters

S308C joins the TM1-boundary cluster (with W314R, H313Y) and introduces a novel thiol regulatory chemistry consideration.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the S308C 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 S308C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A