S308C
Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorialSerine → 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
Bond changes · DynaMut2 interaction analysis
| 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
- pLDDT 61.47 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Optic atrophy / optic neuropathy (autosomal dominant). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
Not attributable to this variant: Congenital bilateral perisylvian syndrome — 4p16.3 contiguous-gene/CNV submissions.
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Also submitted under Congenital bilateral perisylvian syndrome — 4p16.3 contiguous-gene/CNV submissions, not attributable to this coding change.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.
Druggability Assessment
Mechanism: hydroxyl-to-thiol substitution near R309. Therapeutic: site-directed at the cytoplasmic-TM1 boundary region.
Why this matters
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.