AP5S1

Summary

AP5S1 (adaptor related protein complex 5 subunit sigma 1, HGNC:15875) is a protein-coding gene on chromosome 20p13, encoding AP-5 complex subunit sigma-1 (Q9NUS5). As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.

Involved in double-strand break repair via homologous recombination and endosomal transport. Located in several cellular components, including late endosome; lysosome; and nucleoplasm. Part of AP-type membrane coat adaptor complex.

Source: NCBI Gene 55317 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 51 total
• MANE Select transcript: NM_018347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15875
Approved symbol	AP5S1
Name	adaptor related protein complex 5 subunit sigma 1
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11168
Ensembl gene	ENSG00000125843
Ensembl biotype	protein_coding
OMIM	614824
Entrez	55317

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000379567, ENST00000379573, ENST00000455742, ENST00000615891, ENST00000620777, ENST00000870773, ENST00000870774, ENST00000870775, ENST00000927141, ENST00000941770

RefSeq mRNA: 3 — MANE Select: NM_018347 NM_001204446, NM_001204447, NM_018347

CCDS: CCDS13070

Canonical transcript exons

ENST00000615891 — 3 exons

Exon	Start	End
ENSE00001044688	3820547	3820758
ENSE00003723736	3823871	3828838
ENSE00003727570	3822102	3822293

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 85.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5679 / max 72.1307, expressed in 1792 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183233	13.5679	1792

Top tissues by expression

265 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.70	gold quality
biceps brachii	UBERON:0001507	84.68	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.24	silver quality
hindlimb stylopod muscle	UBERON:0004252	84.13	gold quality
vastus lateralis	UBERON:0001379	83.83	silver quality
apex of heart	UBERON:0002098	83.72	gold quality
quadriceps femoris	UBERON:0001377	83.18	silver quality
gastrocnemius	UBERON:0001388	82.33	gold quality
muscle of leg	UBERON:0001383	82.29	gold quality
muscle organ	UBERON:0001630	82.29	gold quality
pancreatic ductal cell	CL:0002079	81.96	silver quality
right adrenal gland cortex	UBERON:0035827	81.73	gold quality
stromal cell of endometrium	CL:0002255	81.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.25	gold quality
right adrenal gland	UBERON:0001233	81.25	gold quality
heart right ventricle	UBERON:0002080	80.86	silver quality
left adrenal gland	UBERON:0001234	80.75	gold quality
skeletal muscle tissue	UBERON:0001134	80.67	gold quality
heart left ventricle	UBERON:0002084	80.44	gold quality
cardiac ventricle	UBERON:0002082	80.31	gold quality
cranial nerve II	UBERON:0000941	80.06	gold quality
left adrenal gland cortex	UBERON:0035825	80.02	gold quality
prefrontal cortex	UBERON:0000451	79.96	gold quality
adrenal cortex	UBERON:0001235	79.56	gold quality
right lobe of liver	UBERON:0001114	79.39	gold quality
nephron tubule	UBERON:0001231	79.38	silver quality
muscle tissue	UBERON:0002385	79.33	gold quality
adrenal gland	UBERON:0002369	78.95	gold quality
tibialis anterior	UBERON:0001385	78.64	silver quality
metanephric glomerulus	UBERON:0004736	78.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting AP5S1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-6879-3P	93.93	64.00	759
HSA-MIR-9899	91.24	59.59	90

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap5s1	ENSDARG00000076755
mus_musculus	Ap5s1	ENSMUSG00000068264
rattus_norvegicus	Ap5s1	ENSRNOG00000021249

Protein

Protein identifiers

AP-5 complex subunit sigma-1 — Q9NUS5 (reviewed: Q9NUS5)

Alternative names: Adaptor-related protein complex 5 sigma subunit

All UniProt accessions (3): Q9NUS5, A2A2L4, Q5JX74

UniProt curated annotations — full annotation on UniProt →

Function. As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862, it is required for efficient homologous recombination DNA double-strand break repair.

Subunit / interactions. Probably part of the adaptor protein complex 5 (AP-5) a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1. Interacts with ZFYVE26 and SPG11.

Subcellular location. Cytoplasm. Cytosol. Late endosome membrane. Lysosome membrane.

RefSeq proteins (3): NP_001191375, NP_001191376, NP_060817* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029392	AP-5_subunit_s1	Family

Pfam: PF15001

UniProt features (1 total): chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8YAB	ELECTRON MICROSCOPY	3.26
8YAH	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NUS5-F1	80.72	0.36

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 96 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOZGIT_ESR1_TARGETS_DN, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_VESICLE_MEDIATED_TRANSPORT, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_DNA_DAMAGE_RESPONSE, GOBP_LYTIC_VACUOLE_ORGANIZATION, GOBP_RECOMBINATIONAL_REPAIR, RASHI_RESPONSE_TO_IONIZING_RADIATION_5, GOCC_LATE_ENDOSOME_MEMBRANE, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_AP_TYPE_MEMBRANE_COAT_ADAPTOR_COMPLEX

GO Biological Process (6): double-strand break repair via homologous recombination (GO:0000724), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), endosomal transport (GO:0016197), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (11): nucleoplasm (GO:0005654), lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), cytosol (GO:0005829), AP-type membrane coat adaptor complex (GO:0030119), late endosome membrane (GO:0031902), AP-5 adaptor complex (GO:0044599), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	2
recombinational repair	1
double-strand break repair	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
vesicle-mediated transport	1
intracellular transport	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
binding	1
nuclear lumen	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
endosome	1
cytoplasm	1
membrane coat	1
membrane protein complex	1
late endosome	1
endosome membrane	1
AP-type membrane coat adaptor complex	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP5S1	AP5B1	Q2VPB7	992
AP5S1	AP5M1	Q9H0R1	980
AP5S1	AP5Z1	O43299	972
AP5S1	SPG11	Q96JI7	952
AP5S1	ZFYVE26	Q68DK2	939
AP5S1	SPTBN4	Q9H254	648
AP5S1	GSTM1	P09488	603
AP5S1	PTPRN2	Q92932	586
AP5S1	AP4M1	O00189	570
AP5S1	SPRN	Q5BIV9	507
AP5S1	PTPRN	Q16849	491
AP5S1	ZBTB3	Q9H5J0	490
AP5S1	ARFGAP2	Q8N6H7	466
AP5S1	ZNF367	Q7RTV3	461
AP5S1	IFT70A	Q86WT1	449

IntAct

19 interactions, top by confidence:

A	B	Type	Score
AP5S1	AP5B1	psi-mi:“MI:0914”(association)	0.800
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
AP5B1	Ap5z1	psi-mi:“MI:0915”(physical association)	0.570
ZFYVE26	AP5Z1	psi-mi:“MI:0914”(association)	0.540
AP5S1	AP5Z1	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
Ap5z1	AP5S1	psi-mi:“MI:0915”(physical association)	0.400
AP5S1	NHERF1	psi-mi:“MI:0914”(association)	0.350
SLC7A9	CDC7	psi-mi:“MI:0914”(association)	0.350
AP5Z1	AP5B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): AP5S1 (Negative Genetic), ZFYVE26 (Affinity Capture-MS), MORF4L1 (Affinity Capture-MS), ACBD6 (Affinity Capture-MS), PRAME (Affinity Capture-MS), AP5B1 (Affinity Capture-MS), MRGBP (Affinity Capture-MS), AP5S1 (Affinity Capture-MS), AP5M1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), SLC9A3R1 (Affinity Capture-MS), COPS6 (Affinity Capture-MS), TNFSF8 (Affinity Capture-MS), COPS3 (Affinity Capture-MS), GPS1 (Affinity Capture-MS)

ESM2 similar proteins: A2XFW2, A2XM23, A8E7G4, C0Z274, F4I2S4, I1MGE5, O01514, O16868, P19862, P86790, P86791, P93527, P93528, Q09417, Q0VD30, Q10150, Q10CQ8, Q10MG9, Q1ZXS5, Q20069, Q28HU2, Q29NZ8, Q4R866, Q4S4I5, Q54IQ5, Q5N8Q4, Q5ZLN2, Q642F4, Q6CCU8, Q6NSW5, Q750L8, Q75EA2, Q7EY72, Q7T102, Q803R2, Q8BH47, Q8C1Y8, Q8TCE6, Q96IW7, Q9D8N2

Diamond homologs: Q9D742, Q9NUS5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP5S1	“form complex”	“AP-5 Adaptor complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

51 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

770 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3820700:GGA:G	donor_gain	1.0000
20:3820701:GAG:G	donor_gain	1.0000
20:3820703:G:GG	donor_gain	1.0000
20:3820754:GTGAC:G	donor_gain	1.0000
20:3820759:G:GG	donor_gain	1.0000
20:3820701:GA:G	donor_gain	0.9900
20:3820751:G:GT	donor_gain	0.9900
20:3820756:GAC:G	donor_gain	0.9900
20:3821803:A:G	donor_gain	0.9900
20:3822088:T:TA	acceptor_gain	0.9900
20:3822096:CTGTA:C	acceptor_loss	0.9900
20:3822098:GTA:G	acceptor_loss	0.9900
20:3822099:TAGCA:T	acceptor_loss	0.9900
20:3822100:A:AG	acceptor_gain	0.9900
20:3822100:A:AT	acceptor_loss	0.9900
20:3822101:G:GA	acceptor_gain	0.9900
20:3822101:GCA:G	acceptor_gain	0.9900
20:3822101:GCACC:G	acceptor_gain	0.9900
20:3822267:G:GT	donor_gain	0.9900
20:3822271:G:GT	donor_gain	0.9900
20:3822292:AGG:A	donor_loss	0.9900
20:3822293:GGTAA:G	donor_loss	0.9900
20:3822294:G:C	donor_loss	0.9900
20:3822295:T:C	donor_loss	0.9900
20:3820669:G:GT	donor_gain	0.9800
20:3820700:G:GT	donor_gain	0.9800
20:3820722:G:GT	donor_gain	0.9800
20:3820748:G:GT	donor_gain	0.9800
20:3822101:GC:G	acceptor_gain	0.9800
20:3822101:GCAC:G	acceptor_gain	0.9800

AlphaMissense

1269 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3824034:T:A	W114R	0.981
20:3824034:T:C	W114R	0.981
20:3824235:T:C	F181L	0.978
20:3824237:C:A	F181L	0.978
20:3824237:C:G	F181L	0.978
20:3822202:T:C	F29L	0.975
20:3822204:C:A	F29L	0.975
20:3822204:C:G	F29L	0.975
20:3824224:G:T	G177V	0.975
20:3822131:T:C	F5S	0.973
20:3822290:C:A	A58D	0.971
20:3822130:T:C	F5L	0.963
20:3822132:C:A	F5L	0.963
20:3822132:C:G	F5L	0.963
20:3824065:T:C	L124P	0.962
20:3824098:C:A	A135D	0.959
20:3824224:G:A	G177D	0.958
20:3824236:T:C	F181S	0.957
20:3824087:C:A	N131K	0.953
20:3824087:C:G	N131K	0.953
20:3822137:T:A	I7N	0.950
20:3822289:G:C	A58P	0.949
20:3822122:T:A	V2D	0.948
20:3824010:T:C	F106L	0.945
20:3824012:C:A	F106L	0.945
20:3824012:C:G	F106L	0.945
20:3822190:T:G	Y25D	0.944
20:3824029:T:A	V112E	0.940
20:3822137:T:C	I7T	0.939
20:3824215:T:C	L174P	0.938

dbSNP variants (sampled 300 via entrez): RS1000060522 (20:3825344 A>T), RS1000495818 (20:3825567 G>C), RS1001345388 (20:3819384 G>A,C), RS1001571467 (20:3821306 A>T), RS1001764948 (20:3827054 C>G), RS1002059830 (20:3821394 CAA>C), RS1002138838 (20:3826796 A>G,T), RS1002670498 (20:3826754 T>C), RS1002863560 (20:3823736 T>C), RS1003266566 (20:3827990 T>G), RS1003278205 (20:3822998 T>A), RS1003400423 (20:3827868 T>C), RS1003708341 (20:3828217 T>C), RS1003840881 (20:3828273 T>C), RS1003879053 (20:3827746 T>G)

Disease associations

OMIM: gene MIM:614824 | disease phenotypes: MIM:234200, MIM:603218

GenCC curated gene-disease

Mondo (2): pantothenate kinase-associated neurodegeneration (MONDO:0009319), Huntington disease-like 1 (MONDO:0011299)

Orphanet (2): Pantothenate kinase-associated neurodegeneration (Orphanet:157850), Huntington disease-like 1 (Orphanet:157941)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006211	Pantothenate Kinase-Associated Neurodegeneration	C10.228.140.079.800; C10.228.140.744.320; C10.228.662.575; C10.574.500.700; C16.320.400.650
C566398	Huntington Disease-Like 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
trichostatin A	affects expression, decreases expression	2
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
SB939 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Panobinostat	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Deoxyglucose	increases expression	1
Methotrexate	increases expression	1
Nickel	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tunicamycin	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01741532	PHASE3	COMPLETED	Efficacy and Safety Study of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN)
NCT02174848	PHASE3	COMPLETED	Long-term Deferiprone Treatment in Patients With Pantothenate Kinase-Associated Neurodegeneration
NCT03041116	PHASE3	TERMINATED	Efficacy and Safety Study of Fosmetpantotenate (RE-024) in PKAN Participants
NCT01838018	Not specified	COMPLETED	Brain Perfusion in Pantothenate Kinase-associated Neurodegeneration (PKAN)
NCT02635841	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Deferiprone in Patients With PKAN
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT04182763	Not specified	COMPLETED	CoA-Z in Pantothenate Kinase-associated Neurodegeneration (PKAN)
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry