AP4S1

Summary

AP4S1 (adaptor related protein complex 4 subunit sigma 1, HGNC:575) is a protein-coding gene on chromosome 14q12, encoding AP-4 complex subunit sigma-1 (Q9Y587). Component of the adaptor protein complex 4 (AP-4).

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.

Source: NCBI Gene 11154 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AP-4 deficiency syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 194 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001128126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:575
Approved symbol	AP4S1
Name	adaptor related protein complex 4 subunit sigma 1
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	CLA20, AP47B, SPG52
Ensembl gene	ENSG00000100478
Ensembl biotype	protein_coding
OMIM	607243
Entrez	11154

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000216366, ENST00000313566, ENST00000334725, ENST00000542754, ENST00000554345, ENST00000554609, ENST00000555417, ENST00000556232, ENST00000556480, ENST00000557346, ENST00000672143, ENST00000673001, ENST00000673317, ENST00000713807, ENST00000713808, ENST00000713810, ENST00000964657, ENST00000964658, ENST00000964659

RefSeq mRNA: 6 — MANE Select: NM_001128126 NM_001128126, NM_001254726, NM_001254727, NM_001254728, NM_001254729, NM_007077

CCDS: CCDS45093, CCDS58309, CCDS58310, CCDS9642

Canonical transcript exons

ENST00000542754 — 6 exons

Exon	Start	End
ENSE00000654733	31069843	31069929
ENSE00001357769	31066126	31066334
ENSE00001610785	31080573	31080584
ENSE00002471290	31092907	31096450
ENSE00003785551	31072905	31072973
ENSE00003889222	31025649	31025787

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 94.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.8276 / max 28.7072, expressed in 1011 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139102	1.6147	919
139101	0.2129	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	94.04	gold quality
calcaneal tendon	UBERON:0003701	93.30	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.38	gold quality
middle temporal gyrus	UBERON:0002771	89.13	gold quality
prefrontal cortex	UBERON:0000451	87.48	gold quality
primary visual cortex	UBERON:0002436	87.45	gold quality
cortical plate	UBERON:0005343	87.12	gold quality
adrenal tissue	UBERON:0018303	86.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.09	gold quality
triceps brachii	UBERON:0001509	85.57	gold quality
colonic epithelium	UBERON:0000397	85.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.21	gold quality
corpus callosum	UBERON:0002336	85.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.88	gold quality
occipital lobe	UBERON:0002021	84.74	gold quality
type B pancreatic cell	CL:0000169	84.53	gold quality
neocortex	UBERON:0001950	84.50	gold quality
frontal cortex	UBERON:0001870	84.43	gold quality
cingulate cortex	UBERON:0003027	84.26	gold quality
olfactory bulb	UBERON:0002264	84.17	gold quality
vena cava	UBERON:0004087	84.15	gold quality
anterior cingulate cortex	UBERON:0009835	84.00	gold quality
germinal epithelium of ovary	UBERON:0001304	83.89	gold quality
right frontal lobe	UBERON:0002810	83.88	gold quality
gluteal muscle	UBERON:0002000	83.81	gold quality
cerebral cortex	UBERON:0000956	83.55	gold quality
nucleus accumbens	UBERON:0001882	83.33	gold quality
tendon	UBERON:0000043	83.23	gold quality
vastus lateralis	UBERON:0001379	83.15	silver quality
biceps brachii	UBERON:0001507	83.07	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	127.52
E-GEOD-111727	no	439.66
E-ANND-3	no	5.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting AP4S1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5010-3P	99.83	70.60	2357

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• Premature stop mutations in AP4S1 result in loss of AP-4 complex assembly and cause fever-sensitive seizures, developmental delay and spastic paraplegia. (PMID:25552650)
• Identification of mutations in AP4S1/SPG52 in hereditary spastic paraplegia. (PMID:27444738)
• Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia. (PMID:31660686)
• Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52. (PMID:32216065)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap4s1	ENSDARG00000054220
mus_musculus	Ap4s1	ENSMUSG00000020955
rattus_norvegicus	Ap4s1	ENSRNOG00000005765

Paralogs (6): AP2S1 (ENSG00000042753), AP1S1 (ENSG00000106367), AP1S3 (ENSG00000152056), AP3S2 (ENSG00000157823), AP3S1 (ENSG00000177879), AP1S2 (ENSG00000182287)

Protein

Protein identifiers

AP-4 complex subunit sigma-1 — Q9Y587 (reviewed: Q9Y587)

Alternative names: AP-4 adaptor complex subunit sigma-1, Adaptor-related protein complex 4 subunit sigma-1, Sigma-1 subunit of AP-4, Sigma-4-adaptin

All UniProt accessions (11): Q9Y587, A0A0G2JL90, A0A5F9ZH42, A0A5F9ZHV3, A0A5F9ZI62, A0A8C8KBR5, A0A8C8KCP6, A0AAQ5BGW5, G3V3X7, G3V4P7, G3V5J6

UniProt curated annotations — full annotation on UniProt →

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. 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.

Subunit / interactions. Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin (sigma-type AP4S1).

Subcellular location. Golgi apparatus. trans-Golgi network membrane.

Tissue specificity. Widely expressed.

Disease relevance. Spastic paraplegia 52, autosomal recessive (SPG52) [MIM:614067] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG52 is characterized by neonatal hypotonia that progresses to hypertonia and spasticity, and severe intellectual disability with poor or absent speech development. Some patients may have seizures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes small subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y587-1	1	yes
Q9Y587-2	2
Q9Y587-3	3
Q9Y587-4	4

RefSeq proteins (6): NP_001121598, NP_001241655, NP_001241656, NP_001241657, NP_001241658, NP_009008 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR016635	AP_complex_ssu	Family
IPR022775	AP_mu_sigma_su	Domain

Pfam: PF01217

UniProt features (4 total): splice variant 3, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9U9I	ELECTRON MICROSCOPY	4
9U9J	ELECTRON MICROSCOPY	4.2
9U9R	ELECTRON MICROSCOPY	6.6
9U9S	ELECTRON MICROSCOPY	6.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y587-F1	94.75	0.94

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 242 (showing top): YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, GGCNKCCATNK_UNKNOWN, chr14q12, MARTINEZ_RB1_TARGETS_UP, GOCC_TRANS_GOLGI_NETWORK, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, YY1_02

GO Biological Process (5): protein targeting (GO:0006605), intracellular protein localization (GO:0008104), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), intracellular protein transport (GO:0006886)

GO Molecular Function (0):

GO Cellular Component (8): trans-Golgi network (GO:0005802), AP-4 adaptor complex (GO:0030124), endosome lumen (GO:0031904), trans-Golgi network membrane (GO:0032588), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	1
Vesicle-mediated transport	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
establishment of protein localization	2
transport	2
intracellular protein localization	2
macromolecule localization	1
cellular process	1
protein transport	1
intracellular transport	1
Golgi apparatus subcompartment	1
AP-type membrane coat adaptor complex	1
endosome	1
intracellular organelle lumen	1
trans-Golgi network	1
organelle membrane	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP4S1	AP4E1	Q9UPM8	999
AP4S1	AP4B1	Q9Y6B7	998
AP4S1	AP4M1	O00189	996
AP4S1	AP3B2	Q13367	718
AP4S1	AP5Z1	O43299	677
AP4S1	RAP2B	P17964	670
AP4S1	ARF3	P16587	669
AP4S1	ARF1	P10947	663
AP4S1	TEPSIN	Q96N21	635
AP4S1	TECPR2	O15040	622
AP4S1	VPS37A	Q8NEZ2	618
AP4S1	SPG21	Q9NZD8	598
AP4S1	DDHD1	Q8NEL9	598
AP4S1	AP1B1	P78436	594
AP4S1	AP3D1	O14617	584

IntAct

24 interactions, top by confidence:

A	B	Type	Score
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
AP4E1	AP4M1	psi-mi:“MI:0914”(association)	0.530
DISC1	AP4M1	psi-mi:“MI:0914”(association)	0.530
AP4S1	HTR6	psi-mi:“MI:0915”(physical association)	0.370
AFP	AP4S1	psi-mi:“MI:0915”(physical association)	0.370
GTF2I	AP4S1	psi-mi:“MI:0915”(physical association)	0.370
AP4S1	TEAD3	psi-mi:“MI:0915”(physical association)	0.370
AP4E1	MAP3K4	psi-mi:“MI:0914”(association)	0.350
AP4M1		psi-mi:“MI:0914”(association)	0.350
AP4S1	RPL10	psi-mi:“MI:0914”(association)	0.350
TEPSIN	DERL1	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
SUV39H2	AP4M1	psi-mi:“MI:0914”(association)	0.350
AP4B1	AP4M1	psi-mi:“MI:0914”(association)	0.350
AP4B1	MYH7B	psi-mi:“MI:0914”(association)	0.350
TGOLN2	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
FGFR1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
GRB2	AP4S1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): AP4S1 (Proximity Label-MS), GALNT2 (Affinity Capture-MS), MECP2 (Affinity Capture-MS), RPL10 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), HLTF (Affinity Capture-MS), TMPO (Affinity Capture-MS), AP4M1 (Affinity Capture-MS), APPBP2 (Affinity Capture-MS), AP4B1 (Affinity Capture-MS), AP4S1 (Affinity Capture-MS), AP4S1 (Affinity Capture-MS), AP4S1 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), CDC73 (Affinity Capture-MS)

ESM2 similar proteins: B0G185, O02173, O17901, O23685, O43041, O50016, O82201, P35181, P35604, P47064, P53290, P53680, P56377, P61923, P61924, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q28IG8, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q557G3, Q59QC5, Q5BFF8, Q5R5F2, Q5R940, Q5ZKP4, Q75F71, Q7SAQ1

Diamond homologs: B0G185, O23685, O50016, O82201, P35181, P47064, P53680, P56377, P59780, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q1JQA3, Q2YDH6, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q5BFF8, Q5R940, Q5RDP9, Q75F71, Q7SAQ1, Q7TN05, Q84WL9, Q8BSZ2, Q8LEZ8, Q8VZ37, Q92572, Q96PC3, Q9DB50

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP4S1	“form complex”	“AP-4 Adaptor complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	72
Likely benign	51
Benign	20

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1423253	NM_001128126.3(AP4S1):c.100_101del (p.Glu34fs)	Pathogenic
1694717	NM_001128126.3(AP4S1):c.146_167del (p.Phe49fs)	Pathogenic
2139018	NM_001128126.3(AP4S1):c.143_144del (p.Ser48fs)	Pathogenic
234925	NM_001128126.3(AP4S1):c.138+3_138+6del	Pathogenic
2581133	NM_001128126.3(AP4S1):c.365_366delinsAG (p.Cys122Ter)	Pathogenic
2732953	NM_001128126.3(AP4S1):c.9dup (p.Phe4fs)	Pathogenic
2804655	NM_001128126.3(AP4S1):c.294+1G>A	Pathogenic
30658	NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)	Pathogenic
3242526	Single allele	Pathogenic
3243950	NC_000014.8:g.(?30046444)(32635573_?)del	Pathogenic
521910	NM_001128126.3(AP4S1):c.229G>T (p.Glu77Ter)	Pathogenic
545037	NM_001128126.3(AP4S1):c.294+1G>C	Pathogenic
577104	NM_001128126.3(AP4S1):c.43C>T (p.Arg15Ter)	Pathogenic
645361	NC_000014.9:g.(?31066187)(31072983_?)del	Pathogenic
997966	GRCh37/hg19 14q12(chr14:27450705-31529481)x3	Pathogenic
1064775	NM_001128126.3(AP4S1):c.138+1G>A	Likely pathogenic
1344800	NM_001128126.3(AP4S1):c.49dup (p.Ser17fs)	Likely pathogenic
1344801	NM_001128126.3(AP4S1):c.139-2A>G	Likely pathogenic
1344802	NM_001128126.3(AP4S1):c.239_240insG (p.Ile80fs)	Likely pathogenic
1479545	NM_001128126.3(AP4S1):c.226-2A>G	Likely pathogenic
1685242	NM_001128126.3(AP4S1):c.295-1G>A	Likely pathogenic
3349945	NM_001128126.3(AP4S1):c.151del (p.Glu51fs)	Likely pathogenic
417874	NM_001128126.3(AP4S1):c.138+2T>G	Likely pathogenic
520786	NM_001128126.3(AP4S1):c.2T>C (p.Met1Thr)	Likely pathogenic
521909	NM_001128126.3(AP4S1):c.17T>C (p.Leu6Pro)	Likely pathogenic

SpliceAI

4227 predictions. Top by Δscore:

Variant	Effect	Δscore
14:31066330:AACAA:A	donor_gain	1.0000
14:31066331:ACAA:A	donor_gain	1.0000
14:31066332:CAA:C	donor_gain	1.0000
14:31066332:CAAG:C	donor_loss	1.0000
14:31066333:AA:A	donor_gain	1.0000
14:31066333:AAG:A	donor_loss	1.0000
14:31066334:AGTAA:A	donor_loss	1.0000
14:31066335:G:GG	donor_gain	1.0000
14:31066336:TAAG:T	donor_loss	1.0000
14:31069838:TCTA:T	acceptor_loss	1.0000
14:31069839:CTAGT:C	acceptor_loss	1.0000
14:31069840:TA:T	acceptor_loss	1.0000
14:31069841:A:AG	acceptor_gain	1.0000
14:31069841:AGT:A	acceptor_gain	1.0000
14:31069842:G:GG	acceptor_gain	1.0000
14:31069842:GT:G	acceptor_gain	1.0000
14:31069842:GTG:G	acceptor_gain	1.0000
14:31069842:GTGCT:G	acceptor_gain	1.0000
14:31072899:TTGTA:T	acceptor_loss	1.0000
14:31072900:TGTA:T	acceptor_loss	1.0000
14:31072901:GTA:G	acceptor_loss	1.0000
14:31072902:TA:T	acceptor_loss	1.0000
14:31072903:A:AG	acceptor_gain	1.0000
14:31072903:AGA:A	acceptor_loss	1.0000
14:31072904:G:GA	acceptor_gain	1.0000
14:31072904:GA:G	acceptor_gain	1.0000
14:31072904:GAAC:G	acceptor_gain	1.0000
14:31072954:A:G	donor_gain	1.0000
14:31072971:GTG:G	donor_gain	1.0000
14:31072974:G:GC	donor_loss	1.0000

AlphaMissense

967 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:31069883:G:C	R60P	0.999
14:31092962:G:T	G121V	0.998
14:31072962:T:C	F95L	0.997
14:31072964:C:A	F95L	0.997
14:31072964:C:G	F95L	0.997
14:31066206:T:C	F4L	0.996
14:31066208:T:A	F4L	0.996
14:31066208:T:G	F4L	0.996
14:31066243:T:C	L16P	0.996
14:31069913:G:A	G70E	0.996
14:31066213:T:C	L6P	0.995
14:31069898:T:C	L65P	0.995
14:31092962:G:A	G121D	0.995
14:31066239:C:G	R15G	0.994
14:31069910:T:A	V69D	0.994
14:31069912:G:A	G70R	0.994
14:31069912:G:C	G70R	0.994
14:31080576:G:A	E100K	0.994
14:31066240:G:C	R15P	0.993
14:31069874:T:C	L57P	0.993
14:31069898:T:A	L65H	0.993
14:31080578:A:C	E100D	0.993
14:31080578:A:T	E100D	0.993
14:31066223:T:A	N9K	0.992
14:31066223:T:G	N9K	0.992
14:31069882:C:G	R60G	0.992
14:31069907:T:A	V68E	0.992
14:31080577:A:T	E100V	0.992
14:31092913:T:C	F105L	0.992
14:31092915:T:A	F105L	0.992

dbSNP variants (sampled 300 via entrez): RS1000031470 (14:31027427 C>T), RS1000173267 (14:31085594 G>T), RS1000187141 (14:31051294 A>G), RS1000225493 (14:31069736 T>C), RS1000283365 (14:31085406 T>C), RS1000318420 (14:31045927 A>C), RS1000365276 (14:31054922 G>A,T), RS1000401224 (14:31085686 T>C), RS1000436698 (14:31067941 T>C), RS1000480654 (14:31059924 CAA>C,CA,CAAA,CAAAA), RS1000522662 (14:31050070 C>A,T), RS1000602469 (14:31025040 C>T), RS1000618785 (14:31084017 A>C), RS1000629702 (14:31091659 T>G), RS1000677111 (14:31026058 G>A)

Disease associations

OMIM: gene MIM:607243 | disease phenotypes: MIM:614067, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 52	Strong	Autosomal recessive
AP4-related intellectual disability and spastic paraplegia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
AP-4 deficiency syndrome	Definitive	AR

Mondo (6): neurodevelopmental disorder (MONDO:0700092), hereditary spastic paraplegia 52 (MONDO:0013552), hereditary spastic paraplegia (MONDO:0019064), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), (MONDO:0017241)

Orphanet (3): Severe intellectual disability and progressive spastic paraplegia (Orphanet:280763), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000297	Facial hypotonia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000646	Amblyopia
HP:0000733	Motor stereotypy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010703_231	Brain morphology (MOSTest)	1.000000e-12
GCST90002392_446	Mean corpuscular volume	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066580 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

1 measured of 3 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
SR 147778	KI	1000 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tretinoin	increases expression, decreases expression	2
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Fluorouracil	decreases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
N-Nitrosopyrrolidine	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5736460	Binding	Human Sigma-1 Receptor Radioligand Assay: To investigate binding properties of test compounds to human Sigma-1 receptor, transfected HEK-293 membranes and 3H-pentazocine (Perkin Elmer, NET-1056), as the radioligand, were used. The assa	Oxadiazaspiro compounds for the treatment of drug abuse and addiction

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E3UV	ESi119-A	Induced pluripotent stem cell	Female
CVCL_E7SZ	SPG FiPS2-Ep6F-8	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants