AP4B1

Summary

AP4B1 (adaptor related protein complex 4 subunit beta 1, HGNC:572) is a protein-coding gene on chromosome 1p13.2, encoding AP-4 complex subunit beta-1 (Q9Y6B7). Component of the adaptor protein complex 4 (AP-4).

This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10717 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AP-4 deficiency syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 468 total — 36 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001253852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:572
Approved symbol	AP4B1
Name	adaptor related protein complex 4 subunit beta 1
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	BETA-4
Ensembl gene	ENSG00000134262
Ensembl biotype	protein_coding
OMIM	607245
Entrez	10717

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 37 protein_coding, 10 nonsense_mediated_decay, 4 retained_intron

ENST00000256658, ENST00000369564, ENST00000369567, ENST00000369569, ENST00000369571, ENST00000432415, ENST00000460653, ENST00000462591, ENST00000472122, ENST00000479285, ENST00000479801, ENST00000484201, ENST00000489092, ENST00000489499, ENST00000713588, ENST00000713590, ENST00000713645, ENST00000713646, ENST00000713647, ENST00000713648, ENST00000713649, ENST00000713650, ENST00000863120, ENST00000863121, ENST00000863122, ENST00000863123, ENST00000863124, ENST00000863125, ENST00000863126, ENST00000863127, ENST00000863128, ENST00000863129, ENST00000863130, ENST00000863131, ENST00000863132, ENST00000935534, ENST00000935535, ENST00000935536, ENST00000935537, ENST00000935538, ENST00000935539, ENST00000935540, ENST00000935541, ENST00000935542, ENST00000935543, ENST00000935544, ENST00000970395, ENST00000970396, ENST00000970397, ENST00000970398, ENST00000970399

RefSeq mRNA: 4 — MANE Select: NM_001253852 NM_001253852, NM_001253853, NM_001308312, NM_006594

CCDS: CCDS76192, CCDS865

Canonical transcript exons

ENST00000369569 — 10 exons

Exon	Start	End
ENSE00001598169	113895757	113896038
ENSE00001717918	113896258	113896465
ENSE00001822605	113899904	113900400
ENSE00003507283	113898718	113898801
ENSE00003574049	113897840	113897943
ENSE00003842339	113894194	113895492
ENSE00004020385	113904605	113904799
ENSE00004020386	113902638	113902862
ENSE00004020388	113901236	113901383
ENSE00004020390	113901755	113901885

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 95.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5717 / max 82.7356, expressed in 1758 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13922	6.6869	1717
13923	1.7151	748
13924	0.1696	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	95.39	gold quality
cerebellar hemisphere	UBERON:0002245	95.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.94	gold quality
cerebellar cortex	UBERON:0002129	94.93	gold quality
cerebellum	UBERON:0002037	94.15	gold quality
thymus	UBERON:0002370	93.30	gold quality
rectum	UBERON:0001052	93.06	gold quality
spleen	UBERON:0002106	92.89	gold quality
body of pancreas	UBERON:0001150	92.65	gold quality
ileal mucosa	UBERON:0000331	92.52	gold quality
right uterine tube	UBERON:0001302	92.46	gold quality
epithelial cell of pancreas	CL:0000083	92.43	silver quality
lymph node	UBERON:0000029	92.21	gold quality
vermiform appendix	UBERON:0001154	91.57	gold quality
right ovary	UBERON:0002118	91.40	gold quality
pituitary gland	UBERON:0000007	91.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.23	gold quality
left ovary	UBERON:0002119	91.10	gold quality
tibia	UBERON:0000979	90.93	gold quality
mucosa of transverse colon	UBERON:0004991	90.62	gold quality
cortical plate	UBERON:0005343	90.56	gold quality
nasal cavity epithelium	UBERON:0005384	90.55	gold quality
transverse colon	UBERON:0001157	90.51	gold quality
adenohypophysis	UBERON:0002196	90.32	gold quality
body of uterus	UBERON:0009853	90.31	gold quality
caecum	UBERON:0001153	90.25	gold quality
ganglionic eminence	UBERON:0004023	90.15	gold quality
embryo	UBERON:0000922	90.14	gold quality
lower esophagus mucosa	UBERON:0035834	90.12	gold quality
small intestine	UBERON:0002108	90.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting AP4B1, 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-4673	100.00	66.64	1490
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-657	99.48	66.02	848
HSA-MIR-569	99.42	66.32	1009

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 7)

• Data suggest that AP4B1 mutations cause spastic paraplegia type 47 and should be considered in early onset spastic paraplegia with intellectual disability. (PMID:22290197)
• Novel homozygous 2-bp deletion in AP4B1 was found in siblings with intellectual disability and spastic tetraplegia. (PMID:24781758)
• AP4B1-associated HSP and other AP-4-deficiency syndromes should be suspected in infants and children with hypotonia progressing to spastic paraplegia, delayed motor and speech development, and suggestive findings on brain imaging particularly thinning of the posterior aspect of the corpus callosum. (PMID:29193663)
• we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development. (PMID:29430868)
• AP4B1 mutation is associated with hereditary spastic paraplegia. (PMID:30337681)
• AP4B1-associated hereditary spastic paraplegia: expansion of phenotypic spectrum related to homozygous p.Thr387fs variant. (PMID:32166732)
• AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range. (PMID:36122674)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap4b1	ENSDARG00000013726
mus_musculus	Ap4b1	ENSMUSG00000032952
rattus_norvegicus	Ap4b1	ENSRNOG00000019455
drosophila_melanogaster	rb	FBGN0003210
caenorhabditis_elegans	apb-3	WBGENE00000163

Paralogs (4): AP2B1 (ENSG00000006125), AP1B1 (ENSG00000100280), AP3B2 (ENSG00000103723), AP3B1 (ENSG00000132842)

Protein

Protein identifiers

AP-4 complex subunit beta-1 — Q9Y6B7 (reviewed: Q9Y6B7)

Alternative names: AP-4 adaptor complex subunit beta, Adaptor-related protein complex 4 subunit beta-1, Beta subunit of AP-4, Beta4-adaptin

All UniProt accessions (13): A0AAA9YHJ8, A0AAA9YHL4, A0AAA9YHP8, A0AAA9YHV6, A0AAQ5BGI8, A0AAQ5BGJ8, A0AAQ5BGK7, A0AAQ5BGL5, Q9Y6B7, A0AAQ5BGN7, B1ALD1, B1ALD2, B1ALD3

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). Interacts with TEPSIN; this interaction requires the presence of a functional AP-4 complex. Interacts with GRIA2; probably indirect it mediates the somatodendritic localization of GRIA2 in neurons.

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

Tissue specificity. Widely expressed.

Disease relevance. Spastic paraplegia 47, autosomal recessive (SPG47) [MIM:614066] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG47 is characterized by neonatal hypotonia that progresses to hypertonia and spasticity, and severe intellectual disability with poor or absent speech development. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes large subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y6B7-1	1	yes
Q9Y6B7-2	2

RefSeq proteins (4): NP_001240781, NP_001240782, NP_001295241, NP_006585 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002553	Clathrin/coatomer_adapt-like_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR012295	TBP_dom_sf	Homologous_superfamily
IPR015151	B-adaptin_app_sub_C	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016342	AP_complex_bsu_1_2_4	Family
IPR026739	AP_beta	Family

Pfam: PF01602, PF09066

UniProt features (21 total): strand 6, mutagenesis site 4, helix 3, splice variant 3, region of interest 2, chain 1, sequence conflict 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9U9I	ELECTRON MICROSCOPY	4
9U9J	ELECTRON MICROSCOPY	4.2
9U9R	ELECTRON MICROSCOPY	6.6
9U9S	ELECTRON MICROSCOPY	6.8
2MJ7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6B7-F1	86.56	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (4):

Position	Phenotype
682	decreased interaction with tepsin.
635	decreased interaction with tepsin.
669	decreased interaction with tepsin; when associated with s-670.
670	decreased interaction with tepsin; when associated with a-669.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 253 (showing top): HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, MODULE_331, GOCC_TRANS_GOLGI_NETWORK, GOCC_COATED_VESICLE, GOCC_GOLGI_ASSOCIATED_VESICLE, GARY_CD5_TARGETS_DN, DANG_BOUND_BY_MYC, RIGGI_EWING_SARCOMA_PROGENITOR_UP, GOCC_CLATHRIN_COATED_VESICLE, GOCC_TRANS_GOLGI_NETWORK_TRANSPORT_VESICLE_MEMBRANE

GO Biological Process (6): protein targeting (GO:0006605), intracellular protein transport (GO:0006886), intracellular protein localization (GO:0008104), vesicle-mediated transport (GO:0016192), protein localization to somatodendritic compartment (GO:0061938), protein transport (GO:0015031)

GO Molecular Function (2): clathrin binding (GO:0030276), protein binding (GO:0005515)

GO Cellular Component (11): trans-Golgi network (GO:0005802), cytosol (GO:0005829), AP-4 adaptor complex (GO:0030124), clathrin adaptor complex (GO:0030131), endosome lumen (GO:0031904), trans-Golgi network membrane (GO:0032588), cytoplasmic side of trans-Golgi network transport vesicle membrane (GO:0098541), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020), membrane coat (GO:0030117)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	2
Vesicle-mediated transport	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1702 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP4B1	AP4M1	O00189	999
AP4B1	AP4S1	Q9Y587	998
AP4B1	AP4E1	Q9UPM8	997
AP4B1	ARF3	P16587	727
AP4B1	RAP2B	P17964	723
AP4B1	ARF1	P10947	721
AP4B1	AP2A1	O95782	698
AP4B1	AP3D1	O14617	667
AP4B1	TEPSIN	Q96N21	655
AP4B1	AP5Z1	O43299	652
AP4B1	VPS37A	Q8NEZ2	607
AP4B1	SPG21	Q9NZD8	603
AP4B1	AP1G1	O43747	600
AP4B1	TECPR2	O15040	588
AP4B1	MTRFR	Q9H3J6	579

IntAct

31 interactions, top by confidence:

A	B	Type	Score
AP4B1	ZNF576	psi-mi:“MI:0915”(physical association)	0.780
ZNF576	AP4B1	psi-mi:“MI:0915”(physical association)	0.780
TEPSIN	AP4B1	psi-mi:“MI:0915”(physical association)	0.770
AP4B1	TEPSIN	psi-mi:“MI:0915”(physical association)	0.770
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
DISC1	AP4M1	psi-mi:“MI:0914”(association)	0.530
AP4E1	AP4M1	psi-mi:“MI:0914”(association)	0.530
AP4B1	FHIP1B	psi-mi:“MI:0914”(association)	0.480
AP4E1	MAP3K4	psi-mi:“MI:0914”(association)	0.350
AP4S1	RPL10	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MYC		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
DISC1	NME2P1	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
POC1A	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
FHIP1A	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
FHIP1B	MED19	psi-mi:“MI:2364”(proximity)	0.270
FIBP	AP4B1	psi-mi:“MI:0915”(physical association)	0.000
ZNF576	AP4B1	psi-mi:“MI:0915”(physical association)	0.000
TEPSIN	AP4B1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): ZNF576 (Two-hybrid), AP4B1 (Proximity Label-MS), AP4B1 (Proximity Label-MS), AP4B1 (Affinity Capture-MS), AP4B1 (Affinity Capture-MS), AP4B1 (Affinity Capture-MS), AP4B1 (Affinity Capture-MS), AP4B1 (Proximity Label-MS), AP4B1 (Proximity Label-MS), AP4B1 (Two-hybrid), ENTHD2 (Two-hybrid), AP4B1 (Affinity Capture-MS), AP4B1 (Two-hybrid), AP4B1 (Phenotypic Enhancement), HOOK1 (Affinity Capture-Western)

ESM2 similar proteins: A0JMW2, A2VE70, A5WW24, A7E2Y6, B9EJR8, E0CZ22, E1BP36, E7FBU4, O35638, O43156, O70576, O75155, Q08AM6, Q0P5A6, Q0V9L1, Q16401, Q5IFJ8, Q5JTH9, Q5R6L5, Q5ZIW5, Q5ZKD5, Q66L58, Q68F38, Q6DCF2, Q6P5B0, Q6ZQ73, Q7TMY7, Q80W92, Q80WQ2, Q84ZC0, Q86Y56, Q8C0Y0, Q8K2V6, Q8NDA8, Q8WVM7, Q91V83, Q96T76, Q99M76, Q9BPX3, Q9D071

Diamond homologs: O35643, O43005, O43079, O81742, P27351, P36000, P52303, P62944, P63009, P63010, Q08DS7, Q10567, Q13367, Q54X82, Q9DBG3, Q9LDK9, Q9SUS3, Q9WV76, Q9Y6B7, O00203, Q32PG1, Q7YRF1, Q9JME5, Q9Z1T1, Q54R84

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP4B1	“form complex”	“AP-4 Adaptor complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	5	21.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	18
Uncertain significance	232
Likely benign	129
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174717	NM_001253852.3(AP4B1):c.444del (p.His148fs)	Pathogenic
1334912	NM_001253852.3(AP4B1):c.1459C>T (p.Arg487Ter)	Pathogenic
1335806	NM_001253852.3(AP4B1):c.1365T>A (p.Tyr455Ter)	Pathogenic
1335882	NM_001253852.3(AP4B1):c.967del (p.Ser323fs)	Pathogenic
1344774	NM_001253852.3(AP4B1):c.304C>T (p.Arg102Ter)	Pathogenic
1362359	NM_001253852.3(AP4B1):c.985A>T (p.Lys329Ter)	Pathogenic
1454422	NM_001253852.3(AP4B1):c.926del (p.Gly309fs)	Pathogenic
1456718	NM_001253852.3(AP4B1):c.1057C>T (p.Arg353Ter)	Pathogenic
1457254	NM_001253852.3(AP4B1):c.352C>T (p.Gln118Ter)	Pathogenic
1526026	NM_001253852.3(AP4B1):c.219C>A (p.Cys73Ter)	Pathogenic
157721	NM_001253852.3(AP4B1):c.313del (p.Ala105fs)	Pathogenic
1703332	NM_001253852.3(AP4B1):c.443_444delinsC (p.His148fs)	Pathogenic
1704352	NM_001253852.3(AP4B1):c.1317dup (p.Ile440fs)	Pathogenic
1993044	NM_001253852.3(AP4B1):c.1122_1123insTTGTAGGTGCCAGGACTTCTTTTGTAGGT (p.Ala375delinsLeuTer)	Pathogenic
1993045	NM_001253852.3(AP4B1):c.1112_1113insGGAGC (p.Ile371fs)	Pathogenic
2008841	NM_001253852.3(AP4B1):c.388_389dup (p.Asp131fs)	Pathogenic
209982	NM_006594.5:c.667del	Pathogenic
210195	NM_001253852.3(AP4B1):c.311_312delinsC (p.Leu104fs)	Pathogenic
2106782	NM_001253852.3(AP4B1):c.876_877del (p.Cys293fs)	Pathogenic
2144496	NM_001253852.3(AP4B1):c.1240C>T (p.Gln414Ter)	Pathogenic
252667	NM_001253852.3(AP4B1):c.114-2A>C	Pathogenic
252668	NM_001253852.3(AP4B1):c.530_531insA (p.Asn178fs)	Pathogenic
2752455	NM_001253852.3(AP4B1):c.1324_1331del (p.Leu442fs)	Pathogenic
2911976	NM_001253852.3(AP4B1):c.444dup (p.Asn149Ter)	Pathogenic
2971411	NM_001253852.3(AP4B1):c.52_53del (p.Cys18fs)	Pathogenic
3632851	NM_001253852.3(AP4B1):c.1098dup (p.Ala367fs)	Pathogenic
4292540	NM_001253852.3(AP4B1):c.1162G>T (p.Glu388Ter)	Pathogenic
434228	NM_001253852.3(AP4B1):c.1490_1503del (p.Arg497fs)	Pathogenic
4531850	NM_001253852.3(AP4B1):c.531_535delinsAGA (p.Asn178fs)	Pathogenic
520648	NM_001253852.3(AP4B1):c.405_409del (p.Tyr135_Arg137delinsTer)	Pathogenic

SpliceAI

1906 predictions. Top by Δscore:

Variant	Effect	Δscore
1:113895493:CTAAA:C	acceptor_loss	1.0000
1:113895494:T:C	acceptor_loss	1.0000
1:113896280:T:TA	donor_gain	1.0000
1:113896290:T:TA	donor_gain	1.0000
1:113896302:G:C	donor_gain	1.0000
1:113898712:CATTA:C	donor_loss	1.0000
1:113898713:ATTAC:A	donor_loss	1.0000
1:113898714:TTAC:T	donor_loss	1.0000
1:113898716:ACCTG:A	donor_loss	1.0000
1:113898798:CCAC:C	acceptor_gain	1.0000
1:113898799:CAC:C	acceptor_gain	1.0000
1:113898799:CACC:C	acceptor_gain	1.0000
1:113898801:CCTA:C	acceptor_loss	1.0000
1:113898802:C:CC	acceptor_gain	1.0000
1:113898802:CTAC:C	acceptor_loss	1.0000
1:113898803:T:C	acceptor_loss	1.0000
1:113900048:CCGAG:C	acceptor_gain	1.0000
1:113900049:C:CT	acceptor_gain	1.0000
1:113900050:G:T	acceptor_gain	1.0000
1:113900052:G:GC	acceptor_gain	1.0000
1:113900326:T:TA	donor_gain	1.0000
1:113900406:C:CT	acceptor_gain	1.0000
1:113900406:C:T	acceptor_gain	1.0000
1:113900407:A:T	acceptor_gain	1.0000
1:113901265:A:AC	donor_gain	1.0000
1:113901280:T:TA	donor_gain	1.0000
1:113901284:T:A	donor_gain	1.0000
1:113901754:CCTA:C	donor_gain	1.0000
1:113902633:CTCA:C	donor_loss	1.0000
1:113902634:TCA:T	donor_loss	1.0000

AlphaMissense

4825 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:113901814:C:A	R137M	1.000
1:113901817:A:T	V136D	1.000
1:113901305:A:G	L183P	0.999
1:113901316:G:C	C179W	0.999
1:113901802:A:T	V141D	0.999
1:113901805:G:T	A140E	0.999
1:113901806:C:G	A140P	0.999
1:113901813:C:A	R137S	0.999
1:113901813:C:G	R137S	0.999
1:113901814:C:G	R137T	0.999
1:113901818:C:A	V136F	0.999
1:113901838:A:G	L129P	0.999
1:113902662:G:T	A105E	0.999
1:113902668:C:T	G103E	0.999
1:113902669:C:A	G103W	0.999
1:113902669:C:G	G103R	0.999
1:113902669:C:T	G103R	0.999
1:113902707:A:G	L90P	0.999
1:113902781:C:A	K65N	0.999
1:113902781:C:G	K65N	0.999
1:113902805:A:C	S57R	0.999
1:113902805:A:T	S57R	0.999
1:113902807:T:G	S57R	0.999
1:113901245:A:G	L203P	0.998
1:113901254:G:T	A200D	0.998
1:113901293:A:G	L187P	0.998
1:113901319:G:C	N178K	0.998
1:113901319:G:T	N178K	0.998
1:113901796:C:T	G143E	0.998
1:113901797:C:G	G143R	0.998

dbSNP variants (sampled 300 via entrez): RS1000235220 (1:113902187 G>A), RS1000449149 (1:113901944 G>A,C), RS1000566827 (1:113906142 C>T), RS1000610333 (1:113897376 A>G), RS1000671626 (1:113906697 G>T), RS1000759357 (1:113904235 T>G), RS1001444801 (1:113898247 T>C), RS1001550726 (1:113905354 C>G,T), RS1001935252 (1:113903733 TAA>T), RS1002330609 (1:113897339 C>G,T), RS1002841535 (1:113906020 G>A), RS1003066087 (1:113896756 C>T), RS1003118265 (1:113896518 C>T), RS1003178469 (1:113904994 G>C,T), RS1003274667 (1:113898648 T>C)

Disease associations

OMIM: gene MIM:607245 | disease phenotypes: MIM:614066, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 47	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): hereditary spastic paraplegia 47 (MONDO:0013551), hereditary spastic paraplegia (MONDO:0019064), intellectual disability (MONDO:0001071), congenital nervous system disorder (MONDO:0002320), AP-4 deficiency syndrome (MONDO:0100176), (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

51 total (30 of 51 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:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000646	Amblyopia
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001762_676	Obesity-related traits	2.000000e-06
GCST001937_47	Breast cancer	2.000000e-08
GCST004132_97	Crohn’s disease	4.000000e-06
GCST004866_5	Alopecia areata	7.000000e-07
GCST007278_4	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	5.000000e-09
GCST90002392_275	Mean corpuscular volume	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Cadmium	increases abundance, increases expression	1
Estradiol	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Urethane	increases expression	1
Zinc	affects cotreatment, increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases expression	1

Cellosaurus cell lines

6 cell lines: 6 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_XJ15	BCHNEUi001-A	Induced pluripotent stem cell	Male
CVCL_XJ16	BCHNEUi002-A	Induced pluripotent stem cell	Male
CVCL_XJ17	BCHNEUi003-A	Induced pluripotent stem cell	Female
CVCL_XJ18	BCHNEUi004-A	Induced pluripotent stem cell	Female
CVCL_XJ19	BCHNEUi005-A	Induced pluripotent stem cell	Female
CVCL_XJ20	BCHNEUi006-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
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
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
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)