P346L

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Proline → Leucine at position 346 · TM2 (340-360), helical transmembrane · WFS1 (Wolframin)

Proline → Leucine at position 346 inside TM2. ClinVar Conflicting with broad clinical spectrum — Wolfram syndrome 1, Cataract 41, Wolfram-like syndrome. AlphaMissense 0.917, ΔΔG -0.62.

Interactive 3D Structure

Wild-type reference

Wild-type P346 — hydrogen bond to F350

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DynaMut2 mutant · P346L

Mutant L346 — hydrogen bond to F343 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F343	—	Lost
Hydrogen bond	I349	I349	Preserved
Hydrogen bond	F350	F350	Preserved
Hydrogen bond	S418	S418	Preserved
Hydrogen bond	—	I421	Gained
Polar contact	A342	A342	Preserved
Polar contact	—	F344	Gained
Polar contact	I349	I349	Preserved
Polar contact	F350	F350	Preserved
Polar contact	—	I421	Gained
Van der Waals	A342	—	Lost
Hydrophobic	I421	I421	Preserved
Hydrophobic	A422	A422	Preserved

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

-0.62kcal/mol

Destabilising — mild

AlphaMissense

0.917

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; Cataract 41; Wolfram-like syndrome

InheritanceWolfram syndrome 1, Wolfram-like syndrome, Cataract 41 documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0014%

cDNA changec.1037C>T

ClinVar accessionVCV000229634

Last evaluated2024/10/26 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 346 sits in TM2. Neighbors: ILE345 (2.5 Å), LEU347 (2.5 Å), ILE349 (4.4 Å — partner of F350I/I349 cluster), PHE344 (4.4 Å). The local environment is uniformly hydrophobic, characteristic of a bilayer-embedded helix interior.

The wild-type proline at 346 likely defines a controlled kink in TM2's middle. Replacing it with leucine removes the kink and lets the helix straighten. The |ΔΔG| of 0.62 reflects modest fold cost; AlphaMissense 0.917 + Wolfram 1 + Cataract 41 confirm severe multi-tissue consequence. The variant is in the broader F350I TM2 cluster.

Amino-acid chemistry

Proline (P) → Leucine (L) — rigid helix-breaking residue replaced by branched aliphatic hydrophobic. Removes backbone constraint.

Position in the protein

TM2 (residues 340–360) · position 346 mid-helix (pLDDT 88).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.62 — fold survives. AlphaMissense 0.917 + three documented phenotypes confirm severe consequence.

Mechanism: loss of TM2 helix kink. Therapeutic: TM2 site-directed (same broader region as F350I).

Why this matters

P346L is the second TM2 variant in the Atlas (with F350I), establishing TM2 as a target region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the P346L 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 P346L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane340–360 · Helical