S430L

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Serine → Leucine at position 430 · TM4 (427-447), helical transmembrane · WFS1 (Wolframin)

Serine → Leucine at position 430 inside TM4. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.932, ΔΔG -0.01 (neutral). Same position as S430W (Atlas card adjacent).

Interactive 3D Structure

Wild-type reference

Wild-type S430 — hydrogen bond to V434

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DynaMut2 mutant · S430L

Mutant L430 — hydrogen bond to G555 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost4 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	A433	Gained
Hydrogen bond	V434	V434	Preserved
Hydrogen bond	G555	—	Lost
Polar contact	P428	P428	Preserved
Polar contact	V434	V434	Preserved
Polar contact	—	G555	Gained
Polar contact	A559	—	Lost
Van der Waals	P428	P428	Preserved
Hydrophobic	—	P428	Gained
Hydrophobic	—	A559	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

0.932

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 syndrome 1

InheritanceWolfram syndrome 1 documented (conflicting classifications).

Population frequency (gnomAD v4)Ultra-rare · AF 0.0025%

cDNA changec.1289C>T

ClinVar accessionVCV001484968

Last evaluated2025/07/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 430 sits in TM4 with the E431 hub contact. Same neighbors as S430W: CYS429 (2.5 Å), GLU431 (2.5 Å — E431 hub), SER551 (4.0 Å — TM4-TM7 cross-helix), PRO428 (4.1 Å), ALA433 (4.4 Å).

S430L is the second substitution at position 430 (with S430W). Where S430W introduced massive aromatic volume, S430L introduces conservative aliphatic volume. The H-bond between S430's hydroxyl and E431's carboxylate is lost in both — same mechanism.

The near-zero ΔΔG indicates fold easily accommodates the more conservative leucine. AlphaMissense 0.932 + Wolfram 1 confirm severe functional consequence.

Amino-acid chemistry

Serine (S) → Leucine (L) — small polar hydroxyl replaced by branched aliphatic hydrophobic. Loss of H-bond capacity; modest volume increase.

Position in the protein

TM4 (residues 427–447) · position 430 near TM4 start (pLDDT 90). Same position as S430W.

Druggability Assessment

Category 3/4 — Most Druggable. ΔΔG ≈ 0 — fold unchanged. AlphaMissense 0.932 confirms severe functional consequence.

Mechanism: loss of S430-E431 H-bond. Therapeutic: same E431 hub target as S430W.

Why this matters

S430L + S430W at same position — both pathogenic, both targeting E431 hub. Drug discovery at E431 has now 6+ convergent variant targets.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the S430L 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 S430L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane427–447 · Helical