AP4E1

Summary

AP4E1 (adaptor related protein complex 4 subunit epsilon 1, HGNC:573) is a protein-coding gene on chromosome 15q21.2, encoding AP-4 complex subunit epsilon-1 (Q9UPM8). Component of the adaptor protein complex 4 (AP-4).

This gene encodes a member of the adaptor complexes large 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 a large subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Disruption of this gene may be associated with cerebral palsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 23431 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AP-4 deficiency syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 658 total — 22 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 59
• MANE Select transcript: NM_007347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:573
Approved symbol	AP4E1
Name	adaptor related protein complex 4 subunit epsilon 1
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	AP-4-EPSILON, SPG51
Ensembl gene	ENSG00000081014
Ensembl biotype	protein_coding
OMIM	607244
Entrez	23431

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000261842, ENST00000558439, ENST00000560508, ENST00000561004, ENST00000561393, ENST00000561397, ENST00000561441, ENST00000879007

RefSeq mRNA: 2 — MANE Select: NM_007347 NM_001252127, NM_007347

CCDS: CCDS32240, CCDS58362

Canonical transcript exons

ENST00000261842 — 21 exons

Exon	Start	End
ENSE00000688557	50923931	50924004
ENSE00000688558	50925098	50925219
ENSE00000688559	50929009	50929168
ENSE00000688560	50930805	50930971
ENSE00000688561	50934624	50934697
ENSE00001102073	51002502	51005895
ENSE00001102077	50915448	50915571
ENSE00003460639	50999072	50999262
ENSE00003502667	50948020	50948159
ENSE00003515423	50912078	50912149
ENSE00003520630	50993370	50993625
ENSE00003521032	51001026	51001183
ENSE00003543407	50950051	50950169
ENSE00003549059	50958492	50958794
ENSE00003578048	50997326	50997883
ENSE00003583155	50941666	50941775
ENSE00003607900	50968263	50968377
ENSE00003608425	50984022	50984145
ENSE00003628664	50941442	50941564
ENSE00003647284	50949826	50949938
ENSE00003848478	50908683	50908928

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 87.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3397 / max 68.7528, expressed in 1796 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146624	10.8943	1793
146623	0.4454	226

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	87.23	gold quality
esophagus squamous epithelium	UBERON:0006920	86.19	gold quality
buccal mucosa cell	CL:0002336	85.92	gold quality
gingiva	UBERON:0001828	85.78	gold quality
palpebral conjunctiva	UBERON:0001812	85.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.54	gold quality
penis	UBERON:0000989	84.34	gold quality
amniotic fluid	UBERON:0000173	84.18	gold quality
calcaneal tendon	UBERON:0003701	83.97	gold quality
epithelium of nasopharynx	UBERON:0001951	83.18	gold quality
tibia	UBERON:0000979	81.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.56	gold quality
tendon	UBERON:0000043	81.37	gold quality
biceps brachii	UBERON:0001507	81.11	gold quality
gastrocnemius	UBERON:0001388	80.39	gold quality
epithelium of esophagus	UBERON:0001976	80.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.19	gold quality
pharyngeal mucosa	UBERON:0000355	80.03	gold quality
upper leg skin	UBERON:0004262	79.91	gold quality
muscle of leg	UBERON:0001383	79.88	gold quality
saphenous vein	UBERON:0007318	79.58	gold quality
monocyte	CL:0000576	79.57	gold quality
body of tongue	UBERON:0011876	79.50	gold quality
mononuclear cell	CL:0000842	79.30	gold quality
leukocyte	CL:0000738	79.22	gold quality
mammalian vulva	UBERON:0000997	79.21	gold quality
squamous epithelium	UBERON:0006914	79.18	gold quality
adrenal tissue	UBERON:0018303	78.75	gold quality
urethra	UBERON:0000057	78.29	gold quality
ventricular zone	UBERON:0003053	78.17	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6911	no	47.12
E-MTAB-4850	no	22.12
E-ANND-3	no	5.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

146 targeting AP4E1, 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-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753

Literature-anchored findings (GeneRIF, showing 8)

• An autosomal recessive form of spastic tetraplegic cerebral palsy with profound intellectual disability, microcephaly, epilepsy and white matter loss in a consanguineous family resulting from a homozygous deletion involving AP4E1. (PMID:20972249)
• The bivalency of the interactions contributes to a higher avidity of tepsin for AP-4. (PMID:26542808)
• Rare Variants in AP4E1 is associated with deficits in intracellular trafficking, and Persistent Stuttering. (PMID:26544806)
• We evaluated 51 stuttering individuals with a mutation in either the GNPTAB, GNPTG, NAGPA, or AP4E1 gene. Mutation carriers achieved significantly less resolution in PSI following therapy, with PSI scores showing significantly less improvement in individuals who carry a mutation (p = 0.0157, RR = 1.75, OR = 2.92) while the group difference in DWS between carriers and non-carriers was statistically not significant. (PMID:31003007)
• Comprehensive genotype-phenotype correlation in AP-4 deficiency syndrome; Adding data from a large cohort of Iranian patients. (PMID:32895917)
• Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. (PMID:32979048)
• A new family with spastic paraplegia type 51 and novel mutations in AP4E1. (PMID:34006278)
• The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia. (PMID:38281682)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap4e1	ENSDARG00000103684
mus_musculus	Ap4e1	ENSMUSG00000001998
rattus_norvegicus	Ap4e1	ENSRNOG00000022938
drosophila_melanogaster	AP-2alpha	FBGN0264855
caenorhabditis_elegans		WBGENE00000161

Paralogs (4): AP1G1 (ENSG00000166747), AP2A2 (ENSG00000183020), AP2A1 (ENSG00000196961), AP1G2 (ENSG00000213983)

Protein

Protein identifiers

AP-4 complex subunit epsilon-1 — Q9UPM8 (reviewed: Q9UPM8)

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

All UniProt accessions (4): Q9UPM8, H0YK94, H0YK95, H0YL95

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. 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 51, autosomal recessive (SPG51) [MIM:613744] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG51 is a non-progressive disorder of movement and/or posture resulting from defects in the developing central nervous system. Affected individuals manifest motor and posture impairments often associated with epilepsy and disturbances of cognition, behavior, sensation, and communication. The disease is caused by variants affecting the gene represented in this entry. Stuttering, familial persistent 1 (STUT1) [MIM:184450] A familial form of stuttering, a disturbance in the normal fluency and time patterning of speech, characterized by frequent repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks. STUT1 inheritance is autosomal dominant. 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?
Q9UPM8-1	1	yes
Q9UPM8-2	2

RefSeq proteins (2): NP_001239056, NP_031373* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002553	Clathrin/coatomer_adapt-like_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR017109	AP4_complex_esu	Family
IPR028269	AP4E1_C	Domain
IPR050840	Adaptor_Complx_Large_Subunit	Family

Pfam: PF01602, PF14807

UniProt features (37 total): sequence variant 25, sequence conflict 7, modified residue 2, chain 1, region of interest 1, splice variant 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-Q9UPM8-F1	72.42	0.25

Functional residue map

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

Post-translational modifications (2): 700, 857

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: 265 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, MORF_ZNF10, GOCC_TRANS_GOLGI_NETWORK, ATGCTGG_MIR338, MORF_EPHA7, MORF_RAB3A, MORF_BMPR2, ELK1_01, MORF_WNT1, CUI_TCF21_TARGETS_2_DN

GO Biological Process (6): protein targeting (GO:0006605), intracellular protein transport (GO:0006886), intracellular protein localization (GO:0008104), vesicle-mediated transport (GO:0016192), protein transport (GO:0015031), establishment of protein localization (GO:0045184)

GO Molecular Function (2): cargo adaptor activity (GO:0140312), protein binding (GO:0005515)

GO Cellular Component (9): 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), 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
cellular anatomical structure	3
establishment of protein localization	2
intracellular protein localization	2
transport	2
cytoplasm	2
protein transport	1
intracellular transport	1
macromolecule localization	1
cellular process	1
establishment of localization	1
vesicle-mediated transport	1
protein-macromolecule adaptor activity	1
binding	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
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

1992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP4E1	AP4S1	Q9Y587	999
AP4E1	AP4B1	Q9Y6B7	997
AP4E1	AP4M1	O00189	995
AP4E1	AP3B2	Q13367	763
AP4E1	ARF1	P10947	721
AP4E1	NAGPA	Q9UK23	688
AP4E1	ARF3	P16587	683
AP4E1	RAP2B	P17964	681
AP4E1	TEPSIN	Q96N21	667
AP4E1	AP5Z1	O43299	642
AP4E1	GNPTG	Q9UJJ9	626
AP4E1	ARCN1	P48444	617
AP4E1	ATG9A	Q7Z3C6	606
AP4E1	SPG21	Q9NZD8	603
AP4E1	COPZ1	P61923	602

IntAct

32 interactions, top by confidence:

A	B	Type	Score
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
AP4E1	TEPSIN	psi-mi:“MI:0915”(physical 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
AP4B1	FHIP1B	psi-mi:“MI:0914”(association)	0.480
AP4E1	HOOK2	psi-mi:“MI:0403”(colocalization)	0.430
POLG2	RPS3	psi-mi:“MI:0914”(association)	0.350
AP4E1	MAP3K4	psi-mi:“MI:0914”(association)	0.350
AP4M1		psi-mi:“MI:0914”(association)	0.350
TEPSIN	DERL1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
ALB	CNOT1	psi-mi:“MI:0914”(association)	0.350
SUV39H2	AP4M1	psi-mi:“MI:0914”(association)	0.350
AP4E1	HOOK3	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
INSR	ATOX1	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TGOLN2	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
	ARHGAP32	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

BioGRID (84): AP4E1 (Affinity Capture-MS), AP4E1 (Proximity Label-MS), AP4E1 (Proximity Label-MS), AP4E1 (Affinity Capture-MS), MAP3K4 (Affinity Capture-MS), TFAP2A (Affinity Capture-MS), AP4M1 (Affinity Capture-MS), AP4B1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), AP4S1 (Affinity Capture-MS), AP4E1 (Affinity Capture-MS), AP4E1 (Affinity Capture-MS), AP4E1 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), ENTHD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JV04, B0V207, D3Z8X7, D3ZFJ3, D3ZND0, F1LM81, G9CGD6, O00499, O08539, O08839, O12940, O60308, O60784, O75674, O88746, P42567, P55194, Q05DH4, Q0GNC1, Q0IHV1, Q27J81, Q3B7M3, Q3UN70, Q4KLN4, Q505K2, Q5FVK6, Q5T0F9, Q5U3K5, Q66HA5, Q68EF0, Q6P1N0, Q6P5E6, Q6P9Q4, Q6P9Q6, Q80V31, Q80V94, Q8BMI3, Q8BRN9, Q8K1A6, Q8R0H9

Diamond homologs: Q54VE0, Q80V94, Q8L7A9, Q9UPM8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP4E1	“form complex”	“AP-4 Adaptor complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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	14.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	15
Uncertain significance	331
Likely benign	192
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031734	NM_007347.5(AP4E1):c.3313C>T (p.Arg1105Ter)	Pathogenic
1419674	NM_007347.5(AP4E1):c.2725G>T (p.Glu909Ter)	Pathogenic
1526453	GRCh37/hg19 15q21.1-21.3(chr15:47635238-56509908)	Pathogenic
1694746	NM_007347.5(AP4E1):c.2659del (p.His887fs)	Pathogenic
1696296	NM_007347.5(AP4E1):c.2804G>A (p.Trp935Ter)	Pathogenic
1944023	NM_007347.5(AP4E1):c.3132_3133del (p.Trp1045fs)	Pathogenic
2423927	NC_000015.9:g.(?50999997)(54025330_?)del	Pathogenic
2579247	GRCh38/hg38 15q21.2(chr15:50923067-50925830)x0	Pathogenic
2685513	GRCh37/hg19 15q21.1-21.3(chr15:49390592-56800964)x1	Pathogenic
3003031	NM_007347.5(AP4E1):c.2327C>G (p.Ser776Ter)	Pathogenic
30659	NC_000015.10:g.50755991_50948682del	Pathogenic
30661	NM_007347.5(AP4E1):c.1359_1360insNN (p.Val454fs)	Pathogenic
3355079	NM_007347.5(AP4E1):c.1096C>T (p.Gln366Ter)	Pathogenic
3668711	NM_007347.5(AP4E1):c.361del (p.Ser121fs)	Pathogenic
3697033	NM_007347.5(AP4E1):c.2215del (p.Glu739fs)	Pathogenic
4279414	GRCh37/hg19 15q21.1-21.2(chr15:47392800-52877953)x1	Pathogenic
4292135	NM_007347.5(AP4E1):c.319C>T (p.Gln107Ter)	Pathogenic
4811746	NM_007347.5(AP4E1):c.1638_1639del (p.Ser547fs)	Pathogenic
564202	GRCh37/hg19 15q21.2-21.3(chr15:50727285-57603305)x3	Pathogenic
569155	NM_007347.5(AP4E1):c.2743_2744insTATGT (p.His915fs)	Pathogenic
688584	GRCh37/hg19 15q21.1-21.3(chr15:49031132-56740397)x3	Pathogenic
988929	GRCh37/hg19 15q21.1-21.3(chr15:48744917-53851050)x1	Pathogenic
1344793	NM_007347.5(AP4E1):c.1358_1359dup (p.Val454fs)	Likely pathogenic
1344795	NM_007347.5(AP4E1):c.652_653del (p.Asp218fs)	Likely pathogenic
1344796	NM_007347.5(AP4E1):c.881_891del (p.Leu294fs)	Likely pathogenic
1344797	NM_007347.5(AP4E1):c.869+1G>A	Likely pathogenic
1344798	NM_007347.5(AP4E1):c.1833del (p.Ser612fs)	Likely pathogenic
1344799	NM_007347.5(AP4E1):c.3277C>T (p.Gln1093Ter)	Likely pathogenic
1699534	NM_007347.5(AP4E1):c.1429+1G>A	Likely pathogenic
1709784	NM_007347.5(AP4E1):c.1558dup (p.Glu520fs)	Likely pathogenic

SpliceAI

4669 predictions. Top by Δscore:

Variant	Effect	Δscore
15:50908925:GCAC:G	donor_gain	1.0000
15:50908929:G:GG	donor_gain	1.0000
15:50912150:G:GG	donor_gain	1.0000
15:50915566:GA:G	donor_gain	1.0000
15:50915568:G:GG	donor_gain	1.0000
15:50915568:GTAG:G	donor_loss	1.0000
15:50915569:TAGGT:T	donor_loss	1.0000
15:50915572:G:C	donor_loss	1.0000
15:50915573:T:A	donor_loss	1.0000
15:50925085:A:AG	acceptor_gain	1.0000
15:50925087:T:G	acceptor_gain	1.0000
15:50925220:G:GG	donor_gain	1.0000
15:50929166:AAGG:A	donor_loss	1.0000
15:50929167:AGGTA:A	donor_loss	1.0000
15:50929168:GGTA:G	donor_loss	1.0000
15:50929169:G:GC	donor_loss	1.0000
15:50929170:T:A	donor_loss	1.0000
15:50941771:GAGAG:G	donor_gain	1.0000
15:50941772:AGAG:A	donor_loss	1.0000
15:50941773:GAG:G	donor_gain	1.0000
15:50941774:AG:A	donor_loss	1.0000
15:50941775:GGTAA:G	donor_loss	1.0000
15:50941777:T:A	donor_loss	1.0000
15:50950047:GTA:G	acceptor_loss	1.0000
15:50950049:A:AG	acceptor_gain	1.0000
15:50950049:A:T	acceptor_loss	1.0000
15:50950050:G:GG	acceptor_gain	1.0000
15:50950159:T:G	donor_gain	1.0000
15:50950165:GTTGG:G	donor_gain	1.0000
15:50950166:T:G	donor_gain	1.0000

AlphaMissense

7447 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:50925102:T:C	L142P	1.000
15:50915539:C:A	A105D	0.999
15:50923931:G:A	G116D	0.999
15:50925138:T:C	L154P	0.999
15:50941669:T:C	L357P	0.999
15:50941678:T:C	L360P	0.999
15:50941732:T:A	I378K	0.999
15:50948030:T:C	L396P	0.999
15:50915527:C:A	A101E	0.998
15:50915571:G:C	G116R	0.998
15:50923939:G:C	A119P	0.998
15:50923940:C:A	A119D	0.998
15:50923982:T:A	L133H	0.998
15:50923997:T:A	V138D	0.998
15:50925135:C:A	A153E	0.998
15:50929020:G:C	R185P	0.998
15:50929028:G:C	A188P	0.998
15:50930916:T:A	W272R	0.998
15:50930916:T:C	W272R	0.998
15:50941532:T:A	V345D	0.998
15:50941564:G:A	G356R	0.998
15:50941564:G:C	G356R	0.998
15:50941666:G:A	G356E	0.998
15:50941732:T:G	I378R	0.998
15:50915476:T:C	L84P	0.997
15:50915526:G:C	A101P	0.997
15:50915563:A:T	K113I	0.997
15:50915564:A:C	K113N	0.997
15:50915564:A:T	K113N	0.997
15:50923982:T:C	L133P	0.997

dbSNP variants (sampled 300 via entrez): RS1000024974 (15:50985236 A>G), RS1000041779 (15:50995923 A>C), RS1000063766 (15:50910756 A>G), RS1000094127 (15:50950411 G>T), RS1000134946 (15:50979051 C>G), RS1000163140 (15:50909388 C>T), RS1000163439 (15:50951788 G>A), RS1000168908 (15:50968544 A>G), RS1000182713 (15:50943248 A>C), RS1000230177 (15:50990173 C>T), RS1000235713 (15:50916803 A>G), RS1000237158 (15:50968179 A>G), RS1000248266 (15:50930046 A>G), RS1000289509 (15:50917171 A>G), RS1000322136 (15:51002825 A>G)

Disease associations

OMIM: gene MIM:607244 | disease phenotypes: MIM:613744, MIM:607143, MIM:184450, MIM:303350, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 51	Definitive	Autosomal recessive
AP-4 deficiency syndrome	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 (9): hereditary spastic paraplegia 51 (MONDO:0013401), ALG12-congenital disorder of glycosylation (MONDO:0011783), congenital nervous system disorder (MONDO:0002320), stuttering, familial persistent, 1 (MONDO:0008483), hereditary spastic paraplegia (MONDO:0019064), AP-4 deficiency syndrome (MONDO:0100176), peripheral neuropathy (MONDO:0005244), congenital myopathy (MONDO:0019952), (MONDO:0017241)

Orphanet (4): Severe intellectual disability and progressive spastic paraplegia (Orphanet:280763), ALG12-CDG (Orphanet:79324), Hereditary spastic paraplegia (Orphanet:685), Congenital myopathy (Orphanet:97245)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000280	Coarse facial features
HP:0000297	Facial hypotonia
HP:0000307	Pointed chin
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000395	Prominent antihelix
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000639	Nystagmus
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:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003485_1	Response to fenofibrate (HDL cholesterol levels)	5.000000e-07
GCST005984_64	Glomerular filtration rate	9.000000e-09
GCST005985_42	Creatinine levels	3.000000e-09
GCST006030_13	Chloride levels	2.000000e-11
GCST006031_10	Potassium levels	5.000000e-24
GCST008839_358	Height	8.000000e-19
GCST90013442_23	Keratoconus	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007805	HDL cholesterol change measurement
EFO:0009283	potassium measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
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
C535745	Congenital disorder of glycosylation type 1G (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Valproic Acid	increases expression, affects expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
coumarin	increases phosphorylation	1
jinfukang	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases mutagenesis	1
Caffeine	decreases phosphorylation	1
Cannabidiol	increases expression	1
Doxorubicin	affects response to substance	1
Estradiol	increases expression	1
Hydrogen Peroxide	increases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Cyclosporine	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SC82	HAP1 AP4E1 (-) 1	Cancer cell line	Male
CVCL_SC83	HAP1 AP4E1 (-) 2	Cancer cell line	Male
CVCL_SC84	HAP1 AP4E1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy