L664R

Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorial

Leucine → Arginine at position 664 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Leucine → Arginine at position 664 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.980, DynaMut2 ΔΔG -0.75 kcal/mol (destabilising). Charge introduction into a hydrophobic position.

Interactive 3D Structure

Wild-type reference

Wild-type L664 — hydrogen bond to S662

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DynaMut2 mutant · L664R

Mutant R664 — van der waals to S662 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S662	S662	Preserved
Hydrogen bond	W700	W700	Preserved
Polar contact	S662	S662	Preserved
Polar contact	W700	W700	Preserved
Van der Waals	S662	—	Lost
Van der Waals	—	W700	Gained
Hydrophobic	Q668	—	Lost
Hydrophobic	Y669	—	Lost
Hydrophobic	L693	—	Lost
Hydrophobic	V698	—	Lost
Hydrophobic	L829	—	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

-0.75kcal/mol

Destabilising — mild

AlphaMissense

0.980

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.

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1991T>G

ClinVar accessionVCV001705303

Last evaluated2022/09/23 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 664 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L664 within 5 Å of THR665 (2.4 Å), THR663 (2.5 Å), GLN668 (3.7 Å — same Q668 as Y669 and L672P environment), SER662 (4.4 Å), and VAL698 (4.9 Å — long-range).

Replacing L664 with arginine introduces a large positive charge into a polar-leaning local environment with H-bonding partners (T665, T663, Q668, S662). The new R664 guanidinium can H-bond with these partners but pulls the local geometry into a new configuration. The Y669-C673-L672-Q668 microregion (densely populated by Atlas variants) is affected.

The |ΔΔG| of 0.75 reflects fold cost. AlphaMissense's 0.980 + Wolfram syndrome 1 confirm severe functional consequence.

Amino-acid chemistry

Leucine (L) → Arginine (R) — branched aliphatic hydrophobic replaced by large positively-charged guanidinium-bearing residue. Charge introduction into a non-polar environment.

Position in the protein

C-terminal lumenal domain · position 664 in the ER lumen (pLDDT 85).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 0.75 — fold survives. AlphaMissense 0.980 + Wolfram 1 confirm severe functional consequence.

Mechanism is charge introduction into the polar 663-665 microregion that abuts the dense Y669-C673 cluster. Therapeutic strategy: site-directed at the polar microregion adjacent to the Y669 cluster.

Why this matters

L664R sits at the edge of the dense Y669-C673-L672 cluster — close enough that drug discovery in the cluster region likely engages L664 as well.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L664R 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 L664R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal