AP2S1
Chr 19ADadaptor related protein complex 2 subunit sigma 1
Also known as: AP17, CLAPS2, FBH3, FBHOk, HHC3
The AP2S1 protein is a component of the adaptor protein complex 2 (AP-2) that functions in clathrin-dependent endocytosis, selectively sorting membrane proteins and forming clathrin-coated vesicles for transport to early endosomes. Mutations cause hypocalciuric hypercalcemia type III, an autosomal dominant disorder affecting calcium homeostasis. The gene shows high constraint against loss-of-function variants (LOEUF 0.502), indicating intolerance to protein-truncating mutations.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
159 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 | 2 | 8 | 0 | 10 |
Likely Pathogenic | 0 | 1 | 2 | 0 | 3 |
VUS | 0 | 29 | 15 | 0 | 44 |
Likely Benign | 0 | 4 | 42 | 35 | 81 |
Benign | 0 | 1 | 9 | 0 | 10 |
Conflicting | — | 4 | |||
| Total | 0 | 37 | 76 | 35 | 152 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
AP2S1 · 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