P504L
Category 3/4 — Most DruggablePathogenicTransmembrane · predictedEditorialProline → Leucine at position 504 inside wolframin's sixth transmembrane helix (TM6). ClinVar Pathogenic with the broadest clinical spectrum in the gene — Wolfram syndrome 1, Wolfram-like syndrome, DFNA6 hearing loss, Cataract 41, type 2 diabetes. AlphaMissense 0.797, DynaMut2 ΔΔG -0.56 kcal/mol (destabilising). One of two adjacent variants (with C505Y) characterizing a vulnerable TM6 region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L484 | — | Lost |
| Hydrogen bond | S502 | S502 | Preserved |
| Hydrogen bond | L507 | L507 | Preserved |
| Hydrogen bond | Y508 | Y508 | Preserved |
| Polar contact | S502 | S502 | Preserved |
| Polar contact | L507 | L507 | Preserved |
| Polar contact | Y508 | Y508 | Preserved |
| Van der Waals | S502 | — | Lost |
| Van der Waals | P885 | — | Lost |
| Hydrophobic | L468 | L468 | Preserved |
| Hydrophobic | P885 | P885 | 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 Pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1; Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome; Wolfram-like syndrome
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Admixed American: AF 0.0067% (4 of 60,010 alleles), 2.4x 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. |
|---|---|---|---|---|
| Admixed American | 0.0067% | 4 / 60,010 | 0 | ~1 in 7500 |
| European (non-Finnish) | 0.0033% | 39 / 1,180,032 | 0 | ~1 in 15130 |
| Remaining individuals | 0.0032% | 2 / 62,458 | 0 | ~1 in 15610 |
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 504 sits inside TM6, immediately adjacent to C505 (Atlas card adjacent). The AlphaFold model places P504 within 5 Å of VAL503 (2.5 Å), CYS505 (2.5 Å), SER502 (4.1 Å), PRO885 (4.1 Å, from TM11 — same cross-helix contact as C505/P885), LEU507 (4.3 Å), and LEU506 (4.5 Å). The proline at position 504 occupies the same structural micro-environment as the C505 next to it, and both contact PRO885 in TM11 at ~4.1 Å.
The wild-type proline at 504 plays a deliberate kinking role in TM6. Just as P885 kinks TM11 (see P885L Atlas card), P504 introduces a controlled helix bend in TM6. This is structurally remarkable: TM6 contains a proline-induced kink at position 504, TM11 contains a proline-induced kink at position 885, and the two kinks face each other across the membrane at the C505/P885 interface. The geometry suggests an intentional structural register that the protein's evolutionary design depends on.
Replacing the TM6 proline with leucine removes the helix kink — TM6 becomes more linear than the wild-type. The PRO885 in TM11 remains in place, but its docking partner across the helix interface has changed shape. The TM6-TM11 register slips. DynaMut2 reports a |ΔΔG| of 0.56 kcal/mol — the fold absorbs it, but the geometric relationship across the helix interface is materially perturbed.
The clinical breadth of P504L (five documented phenotypes spanning both AD and AR Wolfram presentations) is striking given the AlphaMissense score of 0.797 is the lowest of any variant in this batch. The disconnect suggests AlphaMissense's training is conservative about proline substitutions; the clinical evidence is overwhelming.
Druggability Assessment
The mechanism is removal of a deliberate TM6 helix kink, slipping the TM6-TM11 register at the C505/P504/P885 interface. The therapeutic strategy is geometric: a small molecule that stabilizes the TM6-TM11 packing in the wild-type kink geometry, ideally engaging both sides of the interface (TM6 and TM11) simultaneously.
Compare with P885L (Atlas card adjacent) for the reciprocal mechanism, and with C505Y for an alternative TM6 substitution at the same interface. Three Atlas variants (P504L, C505Y, P885L) converge on a single therapeutic target.
Why this matters
Feed this card to Wolfram Intelligence
Download the P504L 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.