L672P
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialLeucine → 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
Bond changes · DynaMut2 interaction analysis
| 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
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 Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Remaining individuals: AF 0.0050% (3 of 60,382 alleles), 10.4x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Remaining individuals | 0.0050% | 3 / 60,382 | 0 | ~1 in 10060 |
| European (non-Finnish) | 0.00036% | 4 / 1,112,004 | 0 | ~1 in 139000 |
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 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.
Druggability Assessment
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
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.