V644L
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialVal→Leu p644 TM10 AM=0.10 ddg=-0.35 pLDDT=82. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L640 | L640 | Preserved |
| Hydrogen bond | — | T641 | Gained |
| Hydrogen bond | C647 | C647 | Preserved |
| Hydrogen bond | W648 | W648 | Preserved |
| Polar contact | L640 | L640 | Preserved |
| Polar contact | T641 | T641 | Preserved |
| Polar contact | C647 | C647 | Preserved |
| Polar contact | W648 | W648 | Preserved |
| Van der Waals | L640 | — | Lost |
| Van der Waals | W648 | W648 | Preserved |
| Hydrophobic | I349 | — | Lost |
| Hydrophobic | F414 | F414 | 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "not specified", "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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00042% (5 of 1,180,048 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| African / African American · under-sampled | 0.0013% | 1 / 74,934 | 0 | — |
| European (non-Finnish) | 0.00042% | 5 / 1,180,048 | 0 | ~1 in 118000 |
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 analysis: ILE643 (2.5 Å), LEU645 (2.5 Å), LEU640 (3.7 Å). Conservative TM10 substitution. The Atlas's neighbor extraction surfaces this variant's contacts.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the V644L 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.