L664R
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialLeucine → 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
Bond changes · DynaMut2 interaction analysis
| 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,996 | 0 | — |
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 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.
Druggability Assessment
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
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.