L672P

Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorial

Leucine → Proline at position 672 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Leucine → Proline at position 672 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.947, DynaMut2 ΔΔG -0.28 kcal/mol (destabilising). A proline-introduction variant adjacent to C673 (the cysteine partner in the C690R disulfide discussion).

Interactive 3D Structure

Wild-type reference

Wild-type L672 — hydrogen bond to Q668

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DynaMut2 mutant · L672P

Mutant P672 — hydrogen bond to Q668 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q668	Q668	Preserved
Hydrogen bond	Y669	—	Lost
Polar contact	Q668	Q668	Preserved
Polar contact	Y669	—	Lost
Polar contact	A677	A677	Preserved
Polar contact	T686	T686	Preserved
Hydrophobic	L689	—	Lost
Hydrophobic	L693	—	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

-0.28kcal/mol

Destabilising — mild

AlphaMissense

0.947

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationLikely pathogenic

Review statuscriteria provided, single submitter

Associated conditions(no specific conditions catalogued)

InheritanceInheritance not specified.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00048%

cDNA changec.2015T>C

ClinVar accessionVCV000918069

Last evaluated2025/07/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 672 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L672 within 5 Å of CYS673 (2.4 Å — same C673 discussed in C690R/C690Y Atlas cards for the inferred disulfide), ALA671 (2.5 Å), TYR669 (3.8 Å — partner of Y669C/Y669H), GLN668 (4.1 Å), and ALA677 (4.5 Å).

The wild-type leucine at 672 contributes hydrophobic packing in a region densely populated by structurally important residues: C673 (potential disulfide), Y669 (aromatic packing partner), Q668. Replacing it with proline introduces a backbone kink that perturbs the geometry of this multi-residue contact cluster.

The |ΔΔG| of 0.28 reflects fold accommodation. AlphaMissense's 0.947 confirms severe functional consequence. The mechanism is geometric — backbone kink propagates through the C673-Y669-Q668 microregion.

Amino-acid chemistry

Leucine (L) → Proline (P) — flexible branched hydrophobic replaced by rigid helix-breaking residue.

Position in the protein

C-terminal lumenal domain · position 672 in the ER lumen (pLDDT 88).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.28 — fold survives. AlphaMissense 0.947 confirms severe functional consequence.

Mechanism is proline-induced backbone kink near the C673-Y669 microregion (shared with Y669C, Y669H, C690R, C690Y atlas cards). Therapeutic strategy: site-directed at this dense contact cluster.

Why this matters

L672P sits adjacent to the C673-Y669-C690 cluster — one of the densest variant-target hubs in the Atlas. Multiple variants converge here, all with site-directed rescue opportunities.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L672P 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 L672P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal