AP4M1

Summary

AP4M1 (adaptor related protein complex 4 subunit mu 1, HGNC:574) is a protein-coding gene on chromosome 7q22.1, encoding AP-4 complex subunit mu-1 (O00189). Component of the adaptor protein complex 4 (AP-4).

This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system.

Source: NCBI Gene 9179 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AP-4 deficiency syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 588 total — 34 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_004722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:574
Approved symbol	AP4M1
Name	adaptor related protein complex 4 subunit mu 1
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MU-ARP2, MU-4, SPG50
Ensembl gene	ENSG00000221838
Ensembl biotype	protein_coding
OMIM	602296
Entrez	9179

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 23 protein_coding, 10 nonsense_mediated_decay, 7 retained_intron

ENST00000359593, ENST00000394061, ENST00000416938, ENST00000421755, ENST00000422582, ENST00000429084, ENST00000438383, ENST00000439416, ENST00000445208, ENST00000445295, ENST00000446007, ENST00000450807, ENST00000463195, ENST00000478501, ENST00000479916, ENST00000489387, ENST00000495154, ENST00000713591, ENST00000713791, ENST00000713792, ENST00000713793, ENST00000713794, ENST00000713795, ENST00000713796, ENST00000713797, ENST00000713798, ENST00000713799, ENST00000907395, ENST00000907396, ENST00000907397, ENST00000918985, ENST00000918986, ENST00000918987, ENST00000970612, ENST00000970613, ENST00000970614, ENST00000970615, ENST00000970616, ENST00000970617, ENST00000970618

RefSeq mRNA: 2 — MANE Select: NM_004722 NM_001363671, NM_004722

CCDS: CCDS5685, CCDS87527

Canonical transcript exons

ENST00000359593 — 15 exons

Exon	Start	End
ENSE00000824885	100101880	100101968
ENSE00003460402	100103612	100103692
ENSE00003465877	100105240	100105346
ENSE00003513974	100105959	100106003
ENSE00003514525	100104874	100104940
ENSE00003539558	100103409	100103519
ENSE00003592557	100105045	100105098
ENSE00003611752	100106241	100106291
ENSE00003643570	100102864	100102960
ENSE00003680628	100104092	100104154
ENSE00003681749	100102675	100102781
ENSE00003785646	100105445	100105539
ENSE00003789291	100106403	100106514
ENSE00004021358	100106658	100109039
ENSE00004021371	100101643	100101772

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 94.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3013 / max 54.2730, expressed in 1747 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79926	4.0167	1637
79925	2.1991	1404
79924	1.0856	709

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.26	gold quality
right testis	UBERON:0004534	94.06	gold quality
right uterine tube	UBERON:0001302	92.35	gold quality
adenohypophysis	UBERON:0002196	90.62	gold quality
cortical plate	UBERON:0005343	90.49	gold quality
testis	UBERON:0000473	90.45	gold quality
stromal cell of endometrium	CL:0002255	90.35	gold quality
body of uterus	UBERON:0009853	90.03	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.21	gold quality
right lobe of thyroid gland	UBERON:0001119	89.19	gold quality
lower esophagus	UBERON:0013473	89.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.11	gold quality
ganglionic eminence	UBERON:0004023	88.87	gold quality
descending thoracic aorta	UBERON:0002345	88.53	gold quality
endocervix	UBERON:0000458	88.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.35	gold quality
pituitary gland	UBERON:0000007	88.35	gold quality
apex of heart	UBERON:0002098	88.30	gold quality
body of stomach	UBERON:0001161	88.13	gold quality
left lobe of thyroid gland	UBERON:0001120	88.12	gold quality
metanephros cortex	UBERON:0010533	88.04	gold quality
ectocervix	UBERON:0012249	87.86	gold quality
tibial nerve	UBERON:0001323	87.79	gold quality
thoracic aorta	UBERON:0001515	87.79	gold quality
ascending aorta	UBERON:0001496	87.74	gold quality
popliteal artery	UBERON:0002250	87.26	gold quality
tibial artery	UBERON:0007610	87.25	gold quality
aorta	UBERON:0000947	87.21	gold quality
left coronary artery	UBERON:0001626	87.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	36.99
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting AP4M1, 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-548N	99.98	71.94	4170
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-6124	99.87	69.78	3551
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-6125	95.17	67.26	91
HSA-MIR-6774-3P	89.14	65.20	68

Literature-anchored findings (GeneRIF, showing 9)

• Results show that AP-4 can bind different types of cytosolic signals known to mediate basolateral transport in epithelial cells. Depletion of mu 4 results in the mis-sorting of several proteins in epithelial cells. (PMID:11802162)
• AP-4 protein complex is involved in the regulation of somatodendritic-specific distribution of its cargo proteins including AMPA receptors. (PMID:18341993)
• In all five patients with autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G–>T), was identified. (PMID:19559397)
• analysis of the AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference [case report] (PMID:25496299)
• Here, the authors demonstrate that dileucine motifs in the hepatitis C virus NS2 protein mediate AP-1A, AP-1B, and AP-4 binding and cell-free virus release. Moreover, they reveal that AP-4, an adaptor not previously implicated in viral infections, mediates cell-to-cell spread and hepatitis C virus trafficking. (PMID:29535204)
• AP4M1 mutation is associated with hereditary spastic paraplegia. (PMID:30337681)
• A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic paraplegia 50. (PMID:33884525)
• Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. (PMID:36371792)
• Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia. (PMID:37758467)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap4m1	ENSDARG00000056871
mus_musculus	Ap4m1	ENSMUSG00000019518
rattus_norvegicus	Ap4m1	ENSRNOG00000001353

Paralogs (7): AP3M2 (ENSG00000070718), AP1M1 (ENSG00000072958), AP1M2 (ENSG00000129354), STON2 (ENSG00000140022), AP2M1 (ENSG00000161203), AP3M1 (ENSG00000185009), STON1 (ENSG00000243244)

Protein

Protein identifiers

AP-4 complex subunit mu-1 — O00189 (reviewed: O00189)

Alternative names: AP-4 adaptor complex mu subunit, Adaptor-related protein complex 4 subunit mu-1, Mu subunit of AP-4, Mu-adaptin-related protein 2, Mu4-adaptin

All UniProt accessions (17): A0AAQ5BGV5, A0AAQ5BGV6, A0AAQ5BGY1, A0AAQ5BGY3, A0AAQ5BGY4, A0AAQ5BGY5, A0AAQ5BGZ1, A0AAQ5BH08, C9JC87, C9JMG3, C9JWL4, O00189, F8WCC5, F8WCR6, F8WDR3, H7BZV3, H7C0A0

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. Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos. The adaptor protein complex 4 (AP-4) 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 tyrosine-based sorting signals on the cytoplasmic tail of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA. Interacts with the C-terminal domain of GRID2. Interacts with GRIA1 and GRIA2; the interaction is indirect via CACNG3. Interacts with CACNG3; CACNG3 associates GRIA1 and GRIA2 with the adaptor protein complex 4 (AP-4) to target them to the somatodendritic compartment of neurons. Interacts with HOOK1 and HOOK2; the interactions are direct, mediate the interaction between FTS-Hook-FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4.

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

Tissue specificity. Ubiquitous. Highly expressed in testis and lowly expressed in brain and lung.

Disease relevance. Spastic paraplegia 50, autosomal recessive (SPG50) [MIM:612936] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG50 affected individuals present postnatally with early infantile hypotonia, delayed psychomotor development, strabismus, lack of independent walking and severe intellectual disability. They develop progressive spasticity of all limbs with generalized hypertonia, hyperreflexia, and extensor plantar responses by the end of the first year of life. Speech is absent or limited. Pseudobulbar signs, such as drooling, stereotypic laughter, and exaggerated jaw jerk, are part of the clinical picture. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes medium subunit family.

RefSeq proteins (2): NP_001350600, NP_004713* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001392	Clathrin_mu	Family
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR018240	Clathrin_mu_CS	Conserved_site
IPR022775	AP_mu_sigma_su	Domain
IPR028565	MHD	Domain
IPR036168	AP2_Mu_C_sf	Homologous_superfamily
IPR050431	Adaptor_comp_med_subunit	Family

Pfam: PF00928, PF01217

UniProt features (28 total): strand 17, sequence conflict 4, turn 2, mutagenesis site 2, chain 1, domain 1, helix 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3L81	X-RAY DIFFRACTION	1.6
4MDR	X-RAY DIFFRACTION	1.85
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-O00189-F1	86.16	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 (2):

Position	Phenotype
255	abolishes interaction with app.
283	strongly reduced interaction with app.

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: 313 (showing top): E2F_Q4, E2F_Q4_01, FREAC2_01, GOBP_LYSOSOMAL_TRANSPORT, E2F4DP1_01, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, FOXO1_01, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (12): autophagosome assembly (GO:0000045), protein targeting (GO:0006605), protein targeting to lysosome (GO:0006622), intracellular protein transport (GO:0006886), post-Golgi vesicle-mediated transport (GO:0006892), Golgi to endosome transport (GO:0006895), intracellular protein localization (GO:0008104), vesicle-mediated transport (GO:0016192), Golgi to lysosome transport (GO:0090160), protein localization to basolateral plasma membrane (GO:1903361), protein transport (GO:0015031), protein transmembrane transport (GO:0071806)

GO Molecular Function (3): transmembrane protein transporter activity (GO:0008320), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (15): early endosome (GO:0005769), trans-Golgi network (GO:0005802), cytosol (GO:0005829), AP-4 adaptor complex (GO:0030124), clathrin adaptor complex (GO:0030131), cytoplasmic vesicle (GO:0031410), endosome lumen (GO:0031904), trans-Golgi network membrane (GO:0032588), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), endosome (GO:0005768), Golgi apparatus (GO:0005794), clathrin-coated pit (GO:0005905), 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	4
cytoplasm	3
endomembrane system	3
establishment of protein localization	2
lysosomal transport	2
intracellular protein localization	2
protein transport	2
cytosolic transport	2
transport	2
endosome	2
AP-type membrane coat adaptor complex	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
protein targeting to vacuole	1
protein localization to lysosome	1
intracellular transport	1
Golgi vesicle transport	1
post-Golgi vesicle-mediated transport	1
intercellular transport	1
macromolecule localization	1
cellular process	1
Golgi to vacuole transport	1
protein localization to membrane	1
protein localization to cell periphery	1
transmembrane transport	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
protein binding	1
binding	1
Golgi apparatus subcompartment	1
clathrin coat	1
intracellular vesicle	1
intracellular organelle lumen	1
trans-Golgi network	1

Protein interactions and networks

STRING

1406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP4M1	AP4B1	Q9Y6B7	999
AP4M1	AP4S1	Q9Y587	996
AP4M1	AP4E1	Q9UPM8	995
AP4M1	SPP1	P10451	946
AP4M1	AP5M1	Q9H0R1	943
AP4M1	GSTM1	P09488	922
AP4M1	ARF1	P10947	833
AP4M1	KANK1	Q14678	797
AP4M1	ARF3	P16587	746
AP4M1	RAP2B	P17964	731
AP4M1	AP3B2	Q13367	722
AP4M1	CD63	P08962	714
AP4M1	SEPSECS	Q9HD40	697
AP4M1	AP1G1	O43747	661
AP4M1	AP1B1	P78436	660

IntAct

47 interactions, top by confidence:

A	B	Type	Score
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
AP4M1	TEPSIN	psi-mi:“MI:0915”(physical association)	0.700
USP47	AP4M1	psi-mi:“MI:0915”(physical association)	0.560
AP4M1	USP47	psi-mi:“MI:0915”(physical association)	0.560
AP4M1	FNTA	psi-mi:“MI:0915”(physical association)	0.560
AP4E1	AP4M1	psi-mi:“MI:0914”(association)	0.530
DISC1	AP4M1	psi-mi:“MI:0914”(association)	0.530
AP4M1	FHIP1A	psi-mi:“MI:0915”(physical association)	0.520
tax	AP4M1	psi-mi:“MI:0915”(physical association)	0.490
AP4M1	HOOK1	psi-mi:“MI:0915”(physical association)	0.370
AP4M1	HOOK2	psi-mi:“MI:0915”(physical association)	0.370
ZBTB22	AP4M1	psi-mi:“MI:0915”(physical association)	0.370
DDX52	AP4M1	psi-mi:“MI:0915”(physical association)	0.370
CHTF8	AP4M1	psi-mi:“MI:0915”(physical association)	0.370
FNTA	AP4M1	psi-mi:“MI:0915”(physical association)	0.370
ECE1	AP4M1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (72): USP47 (Two-hybrid), AP4M1 (Affinity Capture-MS), ACY1 (Affinity Capture-MS), AKT2 (Affinity Capture-MS), GALNT2 (Affinity Capture-MS), H3F3A (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), IMPDH2 (Affinity Capture-MS), NPAT (Affinity Capture-MS), RALA (Affinity Capture-MS), CBX4 (Affinity Capture-MS), AP4M1 (Affinity Capture-MS), AP4M1 (Affinity Capture-MS), AP4M1 (Affinity Capture-MS), LCMT2 (Affinity Capture-MS)

ESM2 similar proteins: A2RV18, A4IG72, A7MB11, B8APQ0, D3ZAA9, E2RED8, E9PY46, F4I562, O00189, O43304, O89043, P33611, P47795, P47823, P53676, P53677, P53678, Q0J649, Q10QS7, Q13144, Q14168, Q14181, Q24K11, Q29RY8, Q2PWT8, Q3UR70, Q499N2, Q4R6Q7, Q58D13, Q5E9X5, Q5R478, Q5ZMP7, Q64350, Q8BJ63, Q8CHW4, Q8R2R9, Q8WUH2, Q93Y22, Q96RY7, Q9D0T2

Diamond homologs: E2RED8, O00189, Q09718, Q29RY8, Q2PWT8, Q9JKC7, Q9SB50, D3ZRP6, O22715, O23140, P35585, P35602, P35603, P54672, P84091, P84092, Q2KJ81, Q32Q06, Q3SYW1, Q3ZC13, Q4R706, Q54HS9, Q5NVF7, Q5ZMP6, Q6NWK2, Q6P856, Q750L8, Q7ZW98, Q801Q8, Q96CW1, Q9BXS5, Q9GPF0, Q9HFE5, Q9SAC9, Q9WVP1, Q9Y6Q5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP4M1	“form complex”	“AP-4 Adaptor complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
protein transport	5	9.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	23
Uncertain significance	240
Likely benign	195
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1180679	NM_004722.4(AP4M1):c.53_54del (p.Lys18fs)	Pathogenic
1285367	NM_004722.4(AP4M1):c.189_194delinsTCTC (p.Tyr65fs)	Pathogenic
1377569	NM_004722.4(AP4M1):c.555_556del (p.Asn185fs)	Pathogenic
1437494	NM_004722.4(AP4M1):c.1320dup (p.Arg441fs)	Pathogenic
1457475	NM_004722.4(AP4M1):c.776_777del (p.Val259fs)	Pathogenic
1497146	NM_004722.4(AP4M1):c.52_58+6del	Pathogenic
1699331	NM_004722.4(AP4M1):c.1012del (p.Arg338fs)	Pathogenic
1701528	NM_004722.4(AP4M1):c.228_231del (p.Phe77fs)	Pathogenic
183357	NM_004722.4(AP4M1):c.952C>T (p.Arg318Ter)	Pathogenic
2047850	NM_004722.4(AP4M1):c.1183_1196del (p.Thr395fs)	Pathogenic
209980	NM_004722.4(AP4M1):c.1012C>T (p.Arg338Ter)	Pathogenic
2143466	NM_004722.4(AP4M1):c.697G>T (p.Glu233Ter)	Pathogenic
2682288	NM_004722.4(AP4M1):c.568del (p.Asp190fs)	Pathogenic
2749126	NM_004722.4(AP4M1):c.861dup (p.Asp288fs)	Pathogenic
280192	NM_004722.4(AP4M1):c.330C>G (p.Tyr110Ter)	Pathogenic
3016128	NM_004722.4(AP4M1):c.63_64del (p.Asp23fs)	Pathogenic
3017395	NM_004722.4(AP4M1):c.403C>T (p.Gln135Ter)	Pathogenic
3245785	NC_000007.13:g.(?99703861)(99704170_?)del	Pathogenic
3245786	NC_000007.13:g.(?99699407)(99704283_?)del	Pathogenic
3775613	NM_004722.4(AP4M1):c.128_132del (p.Asp43fs)	Pathogenic
429735	NM_004722.4(AP4M1):c.923C>G (p.Ser308Ter)	Pathogenic
450738	NM_004722.4(AP4M1):c.842_843del (p.Val281fs)	Pathogenic
450739	NM_004722.4(AP4M1):c.218dup (p.Asn73fs)	Pathogenic
4687481	NC_000007.13:g.(99703627_99703863)_(99704138_99704280)del	Pathogenic
4721295	NM_004722.4(AP4M1):c.912G>A (p.Trp304Ter)	Pathogenic
4813589	NM_004722.4(AP4M1):c.893T>C (p.Leu298Pro)	Pathogenic
496933	NM_004722.4(AP4M1):c.737del (p.Pro246fs)	Pathogenic
520808	NM_004722.4(AP4M1):c.727G>A (p.Gly243Ser)	Pathogenic
522944	NM_004722.4(AP4M1):c.802C>T (p.Arg268Ter)	Pathogenic
561150	NM_004722.4(AP4M1):c.916C>T (p.Arg306Ter)	Pathogenic

SpliceAI

2707 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100101262:AC:A	donor_gain	1.0000
7:100101263:CC:C	donor_gain	1.0000
7:100101263:CCCTT:C	donor_gain	1.0000
7:100101279:AGT:A	donor_gain	1.0000
7:100101769:GACT:G	donor_gain	1.0000
7:100102644:A:AG	acceptor_gain	1.0000
7:100102645:A:G	acceptor_gain	1.0000
7:100102646:C:CA	acceptor_gain	1.0000
7:100102661:T:A	acceptor_gain	1.0000
7:100102665:T:A	acceptor_gain	1.0000
7:100102667:T:TA	acceptor_gain	1.0000
7:100102673:A:AG	acceptor_gain	1.0000
7:100102674:G:GC	acceptor_gain	1.0000
7:100102674:GC:G	acceptor_gain	1.0000
7:100103401:A:AG	acceptor_gain	1.0000
7:100103402:C:G	acceptor_gain	1.0000
7:100103404:A:AG	acceptor_gain	1.0000
7:100103404:ACTAG:A	acceptor_gain	1.0000
7:100103405:CTA:C	acceptor_loss	1.0000
7:100103407:AG:A	acceptor_gain	1.0000
7:100103407:AGG:A	acceptor_loss	1.0000
7:100103408:GG:G	acceptor_gain	1.0000
7:100103408:GGA:G	acceptor_gain	1.0000
7:100103408:GGAC:G	acceptor_gain	1.0000
7:100103408:GGACT:G	acceptor_gain	1.0000
7:100103515:GCTTG:G	donor_gain	1.0000
7:100103520:G:GA	donor_loss	1.0000
7:100103520:G:GG	donor_gain	1.0000
7:100103521:T:G	donor_loss	1.0000
7:100103610:A:AG	acceptor_gain	1.0000

AlphaMissense

2917 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100102944:T:C	L112P	0.999
7:100104110:T:C	F188L	0.999
7:100104112:T:A	F188L	0.999
7:100104112:T:G	F188L	0.999
7:100105460:T:G	Y284D	0.999
7:100105497:T:C	F296S	0.999
7:100106464:T:A	W363R	0.999
7:100106464:T:C	W363R	0.999
7:100106787:T:C	F423L	0.999
7:100106789:C:A	F423L	0.999
7:100106789:C:G	F423L	0.999
7:100103416:G:A	G120D	0.998
7:100103416:G:T	G120V	0.998
7:100104901:G:A	G212R	0.998
7:100104901:G:C	G212R	0.998
7:100105060:T:C	L230S	0.998
7:100106466:G:C	W363C	0.998
7:100106466:G:T	W363C	0.998
7:100106510:T:C	F378S	0.998
7:100106745:T:C	F409L	0.998
7:100106747:C:A	F409L	0.998
7:100106747:C:G	F409L	0.998
7:100103415:G:C	G120R	0.997
7:100103446:T:C	L130P	0.997
7:100104126:A:T	E193V	0.997
7:100104902:G:A	G212E	0.997
7:100104914:T:C	L216P	0.997
7:100105054:T:A	I228N	0.997
7:100105276:T:C	F255S	0.997
7:100105302:T:C	F264L	0.997

dbSNP variants (sampled 300 via entrez): RS1000938909 (7:100103411 C>T), RS1001010924 (7:100100965 C>G,T), RS1001391263 (7:100103153 C>A,G), RS1001397202 (7:100100638 G>A,C,T), RS1001994210 (7:100104516 C>A,G), RS1001999947 (7:100100068 C>A,G,T), RS1002081982 (7:100108169 A>C,G), RS1002114496 (7:100100321 G>A,C,T), RS1002155250 (7:100109361 A>C), RS1002360932 (7:100099279 A>G), RS1002449179 (7:100108973 A>G), RS1002943469 (7:100105821 T>C), RS1003006793 (7:100100774 C>A,G,T), RS1003121401 (7:100100903 T>A,C), RS1003322020 (7:100102274 C>G,T)

Disease associations

OMIM: gene MIM:602296 | disease phenotypes: MIM:612936, MIM:617126, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 50	Definitive	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 (8): hereditary spastic paraplegia 50 (MONDO:0013048), Alazami-Yuan syndrome (MONDO:0014931), congenital nervous system disorder (MONDO:0002320), hereditary spastic paraplegia (MONDO:0019064), AP-4 deficiency syndrome (MONDO:0100176), microcephaly (MONDO:0001149), intellectual disability (MONDO:0001071), (MONDO:0017241)

Orphanet (4): Severe intellectual disability and progressive spastic paraplegia (Orphanet:280763), Alazami-Yuan syndrome (Orphanet:694946), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

54 total (30 of 54 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:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000543	Optic disc pallor
HP:0000646	Amblyopia
HP:0000733	Motor stereotypy
HP:0001181	Adducted thumb
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010002_259	Refractive error	3.000000e-16
GCST010702_48	Subcortical volume (MOSTest)	6.000000e-10
GCST010703_289	Brain morphology (MOSTest)	6.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
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
C567858	Spastic Paraplegia-50, Autosomal Recessive (supp.)

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
Valproic Acid	affects expression, decreases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases methylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases expression	1
Diazinon	increases methylation	1
Drugs, Chinese Herbal	increases expression	1
Naphthoquinones	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Thiram	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases 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_A8KX	BCHNEUi007-A	Induced pluripotent stem cell	Male
CVCL_A8KY	BCHNEUi008-A	Induced pluripotent stem cell	Male
CVCL_A8KZ	BCHNEUi009-A	Induced pluripotent stem cell	Male
CVCL_A8LA	BCHNEUi010-A	Induced pluripotent stem cell	Male
CVCL_A8LB	BCHNEUi011-A	Induced pluripotent stem cell	Male
CVCL_A8LC	BCHNEUi012-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

262 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
NCT06692712	PHASE3	RECRUITING	Phase 3 Efficacy Study With Concurrent Control of IT MELPIDA in SPG50.Concurrent Controls.
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)
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
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
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