AP1S3
Chr 2ADadaptor related protein complex 1 subunit sigma 3
Also known as: PSORS15, sigma1C
The AP1S3 protein is a subunit of clathrin-associated adaptor protein complex 1 that mediates protein sorting in the late-Golgi/trans-Golgi network and endosomes, including trafficking of TLR3. Mutations cause autosomal dominant pustular psoriasis (psoriasis 15), which primarily affects the skin rather than the nervous system. This gene shows low constraint to loss-of-function variants (pLI 0.016, LOEUF 1.079), suggesting it may not be associated with severe developmental disorders.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
78 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 30 | 0 | 30 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 0 | 12 | 5 | 0 | 17 |
Likely Benign | 0 | 5 | 7 | 2 | 14 |
Benign | 0 | 1 | 8 | 0 | 9 |
| Total | 0 | 18 | 51 | 2 | 71 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
AP1S3 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools