P885L
Category 3/4 — Most DruggablePathogenic/Likely pathogenicTransmembrane · predictedEditorialProline → Leucine at position 885 inside wolframin's eleventh and final transmembrane helix (TM11). ClinVar Pathogenic/Likely pathogenic with the broadest clinical spectrum documented for any single position in the gene: Wolfram syndrome 1, Wolfram-like syndrome, DFNA6 hearing loss, Cataract 41, type 2 diabetes. AlphaMissense 0.971, DynaMut2 ΔΔG -0.50 kcal/mol (destabilising).
Reviewed by an affected-family domain expert
The card describes P885L's ClinVar condition list ('Wolfram syndrome 1; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome') as 'the broadest clinical spectrum documented for any single position.' These are SUBMITTED conditions, not documented findings — the list mixes review tiers and includes unverified single-submitter entries. Per expert review, heterozygous (single-copy) P885L carriers in known families are asymptomatic; do not report submitted conditions (e.g. Cataract 41, deafness) as documented phenotypes of single-variant carriers, and do not generalize P885L's presentation to or from nearby variants. Phenotype claims require published case documentation for this exact variant, stratified by ClinVar review status.
Dr. Sarah Gladstone · 2026-08-14 · ClinVar VCV000437297 (review status applies to classification, not per-condition submissions)
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N500 | — | Lost |
| Hydrogen bond | — | C505 | Gained |
| Hydrogen bond | — | F883 | Gained |
| Polar contact | — | P504 | Gained |
| Polar contact | — | F883 | Gained |
| Van der Waals | P504 | — | Lost |
| Van der Waals | — | Y508 | Gained |
| Hydrophobic | — | A465 | Gained |
| Hydrophobic | P504 | P504 | Preserved |
| Hydrophobic | — | Y508 | Gained |
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/Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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 European (non-Finnish): AF 0.0086% (102 of 1,180,050 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) | 0.0086% | 102 / 1,180,050 | 0 | ~1 in 5780 |
| South Asian | 0.0033% | 3 / 91,094 | 0 | ~1 in 15180 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,474 | 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 885 sits inside TM11, the final transmembrane helix of wolframin. The AlphaFold model places P885 within 5 Å of PHE886 (2.5 Å), PHE884 (2.5 Å), PHE883 (4.2 Å), and LEU887 (4.7 Å). The local environment is dominated by aromatic residues — an aromatic cluster (F883, F884, F886) within a single membrane-embedded turn of helix.
The wild-type proline at position 885 is structurally deliberate. Proline residues in transmembrane helices appear in specific positions where the protein needs the helix to kink — they introduce a controlled bend in what would otherwise be a straight α-helix. Proline at position 885, sitting in the middle of three consecutive phenylalanines, almost certainly serves this kinking role: it creates a controlled local geometry that the surrounding aromatic packing depends on.
Replacing proline with leucine removes that controlled kink. Leucine cannot break the helix in the same way — its backbone is free to adopt the standard α-helical phi/psi angles. The result is a TM11 that is more linear than the wild-type, with the aromatic cluster (F883, F884, F886) reorganized accordingly. The interlocking packing that depends on the wild-type kink is lost.
The |ΔΔG| of 0.50 kcal/mol indicates the fold absorbs this rearrangement — TM11 still embeds in the membrane, the protein still folds. But the precise geometry of the C-terminal anchoring region is changed, and the AlphaMissense score of 0.971 reflects severe functional consequence. Notably, C505Y (Atlas card adjacent, in TM6) has PRO885 as a 4.1 Å neighbor — suggesting TM6-TM11 cross-talk in the membrane. Disrupting the P885 kink also affects whatever functional contact TM6 makes through this position.
Druggability Assessment
The mechanism is loss of a deliberate proline-induced helix kink in TM11, perturbing the C-terminal membrane anchoring geometry and disrupting the TM6-TM11 cross-helix contact through C505/P885 (see C505Y Atlas card for the reciprocal view).
The therapeutic strategy is site-directed at the TM11 aromatic cluster: a small molecule that restores the helix geometry the wild-type kink produced, or that occupies the disrupted TM6-TM11 interface, would compensate for the lost kink. The clinical breadth (five distinct phenotypes documented) makes this one of the highest-value docking targets in the WFS1 atlas.
Why this matters
Feed this card to Wolfram Intelligence
Download the P885L 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.