P607R
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialProline → Arginine at position 607 inside TM9. ClinVar Conflicting. AlphaMissense 0.922, ΔΔG +0.03 (neutral). pLDDT 66 borderline. Proline-removal in TM9 with charge introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | C604 | — | Lost |
| Hydrogen bond | L610 | L610 | Preserved |
| Hydrogen bond | R611 | R611 | Preserved |
| Polar contact | V603 | — | Lost |
| Polar contact | C604 | — | Lost |
| Polar contact | L610 | L610 | Preserved |
| Polar contact | R611 | R611 | Preserved |
| Van der Waals | R611 | — | 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
- transmembrane position; predictor benchmarked on soluble proteins
- pLDDT 65.88 below 70
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.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
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 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 0.00076% (9 of 1,180,022 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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00076% | 9 / 1,180,022 | 0 | ~1 in 65560 |
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 607 sits near the end of TM9. Neighbors: LEU608 (2.5 Å), VAL606 (2.5 Å), LEU610 (4.1 Å), SER605 (4.5 Å).
The wild-type proline likely defines a helix-end geometry. Replacing it with arginine removes the kink and introduces charge near the membrane-water interface. The near-zero ΔΔG reflects fold accommodation through the arginine extending toward solvent.
AlphaMissense 0.922 confirms severe consequence. P607L (Atlas card next) is the same position with leucine — both pathogenic.
Druggability Assessment
Mechanism: loss of TM9 helix-end kink plus charge introduction. Therapeutic: site-directed at the TM9 C-terminal region.
Why this matters
Feed this card to Wolfram Intelligence
Download the P607R 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.