AP1S2

Chr XXLR

adaptor related protein complex 1 subunit sigma 2

NCBI Gene: 8905ENSG00000182287UniProt: P56377

Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules

Primary Disease Associations & Inheritance

Pettigrew syndromeMIM #304340
XLR
299
ClinVar variants
0
Pathogenic / LP
0.87
pLI score
0
Active trials
Clinical Summary— AP1S2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.
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ClinVar Variants
299 total variants — no pathogenic classifications of 299 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.45LOEUF
pLI 0.867
Z-score 2.38
OE 0.00 (0.00–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.01Z-score
OE missense 0.26 (0.17–0.40)
15 obs / 58.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.26 (0.17–0.40)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.12
0≤1.21.6
LoF obs/exp: 0 / 6.6Missense obs/exp: 15 / 58.2Syn Z: -0.42

ClinVar Variant Classifications

299 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

AP1S2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AP1S2-related intellectual developmental disorder

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pettigrew syndrome

MIM #304340

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms.
Liu XY et al.·Mil Med Res
2024Review
Chromosome X-wide common variant association study in autism spectrum disorder.
Mendes M et al.·Am J Hum Genet
2025
A novel splice site mutation in AP1S2 gene for X-linked mental retardation in a Chinese pedigree and literature review.
Huo L et al.·Brain Behav
2019Review
The neurodevelopmental spectrum of synaptic vesicle cycling disorders.
John A et al.·J Neurochem
2021Review
A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability.
Noojarern S et al.·Am J Med Genet A
2024
Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome.
Borck G et al.·Hum Mutat
2008
Single-cell and machine learning integration reveals ferroptosis-driven immune landscapes for melanoma stratification.
Wang L et al.·Front Immunol
2025
Identification of a 5 bp duplicate in the AP1S2 gene of an individual with X-linked intellectual disability.
Zhu D et al.·Neurogenetics
2022Case report
AP1S2-truncating variant in a patient with severe neurodevelopmental disorder and cerebral folate deficiency.
Cappuccio G et al.·Acta Paediatr
2019Case report
Next-generation sequencing in X-linked intellectual disability.
Tzschach A et al.·Eur J Hum Genet
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools