GeneBe

AP1S2

protein-coding

adaptor related protein complex 1 subunit sigma 2, the group of Adaptor related protein complex 1

Gene summary

Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as the small subunit of this complex and is a member of the adaptin protein family. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

Previous symbols:
  • MRX59
  • MRXS5
  • PGS

MANE transcript

NM_001272071.2

Inheritance

XL

ClinVar variants

P:24U:41B:17

Top phenotype

Pettigrew syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:15,825,806-15,854,931

External References & Databases

Ensembl (ENSG00000182287)NCBI Gene (8905)OMIM (300629)HGNC:560GenCCUniProt (P56377)AlphaFoldClinVar (AP1S2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~29.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fried syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019428

Submitter: Orphanet

syndromic X-linked intellectual disability 5DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: G2P

syndromic X-linked intellectual disability 5SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: Orphanet

syndromic X-linked intellectual disability 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: PanelApp Australia

syndromic X-linked intellectual disability 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: Labcorp Genetics (formerly Invitae)

X-linked syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:1040018

Submitter: ClinGen

*AP1S2* was first reported in relation to X-linked syndromic complex neurodevelopmental disorder in 2006 (Tarpey et al., PMID: 17186471). *AP1S2* encodes the sigma 2 subunit of the adaptor protein 1 (AP1) complex. AP1 is found in coated vesicles in the Golgi compartment, where it mediates the recruitment of clathrin and the recognition of sorting signals of transmembrane receptors. The clinical features in affected males are highly variable and may include hypotonia, intellectual disability, autism spectrum disorder, seizures, choreoathetosis, microcephaly, and brain malformations such as hydrocephalus, periventricular nodular heterotopia, basal ganglia calcifications, Dandy-Walker malformation, and cerebellar defects. Seven variants (nonsense and splice) that have been reported in eight probands in five publications (PMIDs: 17186471, 17617514, 18428203, 23756445, 25649377) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by biochemical function, protein interactions, and a mouse model. Pathogenic variants in other subunits of the AP1 complex are also involved in neurodevelopmental disorders, including *AP1S1*, *AP1B1*, and *AP1G1*. In summary, there is definitive evidence supporting the relationship between *AP1S2* and X-linked syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on April 22, 2025 (SOP Version 11). Although new experimental evidence was added, the classification did not change.

autism spectrum disorderLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

syndromic X-linked intellectual disability 5MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: Ambry Genetics

syndromic X-linked intellectual disability 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010574

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Pettigrew syndromeXL

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 5054319; 10398241; 12599187; 17617514; 18428203; 19377476; 2018058; 22210230; 23756445Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP1S2 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 64
Pettigrew syndromeTotal: 20
not specifiedTotal: 10
Inborn genetic diseasesTotal: 10
AP1S2-related disorderTotal: 4
X-linked syndromic intellectual disabilityTotal: 1
Fried syndromeTotal: 1
Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001272071.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
14
clinvar
2
clinvar
 20
missense
31
clinvar
1
clinvar
 32
nonsense
7
clinvar
1
clinvar
2
clinvar
 10
start loss
0
frameshift
4
clinvar
5
clinvar
 9
splice donor/acceptor (+/-2bp)
5
clinvar
2
clinvar
4
clinvar
 11
Total1684115282

Highest pathogenic variant AF is 0.0000016118036

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001272071.2RefSeqNP_001259000.15MANE Select
ENST00000672987.1EnsemblENSP00000500695.15MANE Select
NM_001368994.1RefSeqNP_001355923.14Standard
NM_001369007.1RefSeqNP_001355936.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Golgi Associated Vesicle Biogenesis
  • Lysosome Vesicle Biogenesis
  • Clathrin derived vesicle budding
  • Disease

Biological Process

  • intracellular protein transport
  • vesicle-mediated transport
  • antigen processing and presentation of exogenous peptide antigen via MHC class II
  • regulation of defense response to virus by virus

Molecular Function

  • protein binding

Cellular Component

  • Golgi membrane
  • lysosomal membrane
  • Golgi apparatus
  • cytosol
  • clathrin-coated pit

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000329235
Coding exons
4
Length
29126
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.011558.20.2580.000004551027
Missense (PolyPhen)518.9510.26384361
Synonymous-0.4252219.61.120.00000137286
Loss of Function2.3806.600.005.37e-7112

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: 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.;

Recessive Scores

pRec
0.0507

Intolerance Scores

RVIS EVS
0.06
RVIS percentile EVS
58

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.846

Gene Damage Prediction

AllRecessiveDominant
MendelianLowLowLow
Primary ImmunodeficiencyLowLowLow
CancerLowLowLow
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