AP4S1

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

Basic information

Region (hg38): 14:31025105-31130996

Links

ENSG00000100478 ∙ NCBI:11154 ∙ OMIM:607243 ∙ HGNC:575 ∙ Uniprot:Q9Y587 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 52 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 52 (Strong), mode of inheritance: AR
• AP4-related intellectual disability and spastic paraplegia (Supportive), mode of inheritance: AR
• AP-4 deficiency syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 52, autosomal recessive	AR	General	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	Craniofacial; Neurologic	21620353

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AP4S1 gene.

• Spastic paraplegia (61 variants)
• not provided (54 variants)
• Inborn genetic diseases (42 variants)
• Spastic paraplegia 52, autosomal recessive (15 variants)
• not specified (12 variants)
• Hereditary spastic paraplegia (6 variants)
• Intellectual disability (2 variants)
• Neurodevelopmental disorder (2 variants)
• AP4S1-related disorder (1 variants)
• APS41-Related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AP4S1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				8		8
missense		1	23	1	1	26
nonsense	3	1	1			5
start loss						0
frameshift	4	1				5
inframe indel						0
splice donor/acceptor (+/-2bp)		5				5
splice region	1		1	2		4
non coding			43	29	23	95
Total	7	8	67	38	24

Highest pathogenic variant AF is 0.00201

Variants in AP4S1

This is a list of pathogenic ClinVar variants found in the AP4S1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-31025782-G-A		not specified	Benign (Apr 15, 2016)
14-31025953-C-A		not specified	Uncertain significance (Sep 20, 2023)
14-31025981-G-C		not specified	Uncertain significance (Oct 05, 2021)
14-31026004-T-C		not specified	Uncertain significance (Sep 17, 2021)
14-31026007-G-C		not specified	Uncertain significance (Aug 01, 2023)
14-31026056-G-A		not specified	Uncertain significance (Jul 19, 2023)
14-31026080-C-T		not specified	Uncertain significance (May 08, 2023)
14-31026088-C-T		not specified	Uncertain significance (Mar 31, 2023)
14-31026101-C-T		not specified	Likely benign (Apr 03, 2023)
14-31065851-A-G			Benign (Jun 14, 2018)
14-31065881-C-T			Likely benign (Aug 15, 2018)
14-31065911-C-T			Benign (Jul 31, 2018)
14-31066198-T-C		Inborn genetic diseases • Spastic paraplegia	Likely pathogenic (Apr 24, 2023)
14-31066201-T-TA		Spastic paraplegia	Pathogenic (Nov 24, 2022)
14-31066213-T-C		Inborn genetic diseases • Spastic paraplegia	Likely pathogenic (Jul 24, 2017)
14-31066217-G-A		not specified	Uncertain significance (Jan 20, 2015)
14-31066225-A-G		not specified • Spastic paraplegia • Spastic paraplegia 52, autosomal recessive • Hereditary spastic paraplegia	Conflicting classifications of pathogenicity (Jan 22, 2024)
14-31066230-G-A		Spastic paraplegia	Uncertain significance (Jul 21, 2022)
14-31066239-C-T		Spastic paraplegia	Pathogenic (Oct 18, 2017)
14-31066240-G-A		Spastic paraplegia 52, autosomal recessive	Uncertain significance (Dec 15, 2022)
14-31066242-C-CT		Spastic paraplegia	Likely pathogenic (Oct 01, 2020)
14-31066263-G-A		Inborn genetic diseases	Uncertain significance (Feb 10, 2022)
14-31066266-G-A		Spastic paraplegia	Uncertain significance (Dec 11, 2023)
14-31066278-C-T		Spastic paraplegia	Uncertain significance (Aug 22, 2022)
14-31066279-G-A		Spastic paraplegia • Spastic paraplegia 52, autosomal recessive	Uncertain significance (Oct 17, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AP4S1	protein_coding	protein_coding	ENST00000216366	5	68507

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000173	0.257	125679	0	56	125735	0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0101	85	84.7	1.00	0.00000423	1054
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000437	0.000437
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000255	0.000255
Middle Eastern	0.000163	0.000163
South Asian	0.000229	0.000229
Other	0.000326	0.000326

dbNSFP

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}.
• Pathway: Lysosome - Homo sapiens (human);Lysosome Vesicle Biogenesis;Clathrin derived vesicle budding;trans-Golgi Network Vesicle Budding;Vesicle-mediated transport;Membrane Trafficking (Consensus)

Intolerance Scores

• loftool: 0.382
• rvis_EVS: -0.36
• rvis_percentile_EVS: 28.63

Haploinsufficiency Scores

• pHI: 0.164
• hipred: N
• hipred_score: 0.177
• ghis: 0.637

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.982

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ap4s1

Gene ontology

• Biological process: protein targeting;protein localization
• Cellular component: AP-4 adaptor complex;endosome lumen;trans-Golgi network membrane;intracellular membrane-bounded organelle