AP4S1

protein-coding

adaptor related protein complex 4 subunit sigma 1, the group of Adaptor related protein complex 4

Gene summary

This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

MANE transcript

NM_001128126.3

Inheritance

ClinVar variants

P:24U:32B:15

Top phenotype

Spastic paraplegia 52, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr14:31,025,106-31,130,996

External References & Databases

Ensembl (ENSG00000100478)

Transcript & Mutation Effects

hg38 • Region Span ~105.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 52STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013552

Submitter: G2P

hereditary spastic paraplegia 52STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013552

Submitter: PanelApp Australia

AP4-related intellectual disability and spastic paraplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017241

Submitter: Orphanet

hereditary spastic paraplegia 52STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013552

Submitter: Labcorp Genetics (formerly Invitae)

AP-4 deficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100176

Submitter: ClinGen

*AP4S1* loss-of-function variants were first reported in relation to autosomal recessive Adaptor Protein 4 (AP-4) deficiency syndrome in 2011 (PMID: 21620353). AP-4 deficiency results in severe early-onset developmental delay with motor and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048). At least 23 individuals from 16 families with biallelic *AP4S1* nonsense, frameshift, splicing and missense variants leading to loss of protein function have been reported (PMIDs: 21620353, 25552650, 32979048). The gene-disease association is further supported by biochemical and functional evidence demonstrating loss of AP-4 complex function and impaired protein localization in fibroblasts from patients with biallelic *AP4S1* loss-of-function variants (PMID: 25552650). Loss of *AP4S1* in zebrafish also results in reduced head size, altered CNS development, locomotor deficits, and abnormal neuronal excitability (PMID: 32216065). In summary, there is definitive evidence supporting the relationship between *AP4S1* and autosomal recessive AP-4 deficiency syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 25, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Spastic paraplegia 52, autosomal recessiveAR

Manifestation: Craniofacial; 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: 21620353

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP4S1 variants in ClinVar

11 Conditions Cataloged

Spastic paraplegiaTotal: 79

not specifiedTotal: 38

not providedTotal: 31

Inborn genetic diseasesTotal: 29

Hereditary spastic paraplegia 52Total: 19

AP4S1-related disorderTotal: 13

Hereditary spastic paraplegiaTotal: 6

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128126.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				13 clinvar		13
missense		1 clinvar	31 clinvar	2 clinvar		34
nonsense	4 clinvar	1 clinvar				5
start loss		1 clinvar				1
frameshift	4 clinvar	3 clinvar				7
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	1 clinvar			11
Total	11	13	32	15	0	71

Highest pathogenic variant AF is 0.0018702288

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001128126.3	RefSeq	NP_001121598.1	5	MANE Select
ENST00000542754.7	Ensembl	ENSP00000438170.2	5	MANE Select
NM_001254726.2	RefSeq	NP_001241655.1	4	Standard
NM_001254727.2	RefSeq	NP_001241656.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding
Vesicle-mediated transport

Biological Process

protein targeting
protein localization

Cellular Component

AP-4 adaptor complex
endosome lumen
trans-Golgi network membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216366
Coding exons: 5
Length: 68507
Individuals with no LoFs: 125679
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125735
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0101	85	84.7	1.00	0.00000423	1054
Missense (PolyPhen)		24	24.6	0.9756		321
Synonymous	-0.390	30	27.4	1.09	0.00000119	286
Loss of Function	0.119	9	9.39	0.958	6.17e-7	93

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways (PubMed:10066790, PubMed:10436028). AP-4 forms a non clathrin- associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable). {ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028, ECO:0000305|PubMed:10066790, ECO:0000305|PubMed:10436028}.;

Intolerance Scores

LoFtool: 0.382
RVIS EVS: -0.36
RVIS percentile EVS: 28.63

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium