ABCD3

Summary

ABCD3 (ATP binding cassette subfamily D member 3, HGNC:67) is a protein-coding gene on chromosome 1p21.3, encoding ATP-binding cassette sub-family D member 3 (P28288). Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that catalyzes the transport of long-chain fatty acids (LCFA)-CoA, dicarboxylic acids-CoA, long-branched-chain fatty acids-CoA and bile acids from the cytosol to the peroxisome lumen f….

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein likely plays an important role in peroxisome biogenesis. Mutations have been associated with some forms of Zellweger syndrome, a heterogeneous group of peroxisome assembly disorders. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 5825 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital bile acid synthesis defect 5 (Moderate, GenCC)
• Clinical variants (ClinVar): 237 total — 2 pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• MANE Select transcript: NM_002858

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:67
Approved symbol	ABCD3
Name	ATP binding cassette subfamily D member 3
Location	1p21.3
Locus type	gene with protein product
Status	Approved
Aliases	PMP70, ZWS2
Ensembl gene	ENSG00000117528
Ensembl biotype	protein_coding
OMIM	170995
Entrez	5825

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 24 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000315713, ENST00000370214, ENST00000464165, ENST00000468860, ENST00000484213, ENST00000493416, ENST00000647998, ENST00000866889, ENST00000866890, ENST00000866891, ENST00000866892, ENST00000866893, ENST00000866894, ENST00000866895, ENST00000866896, ENST00000866897, ENST00000866898, ENST00000917833, ENST00000966692, ENST00000966693, ENST00000966694, ENST00000966695, ENST00000966696, ENST00000966697, ENST00000966698, ENST00000966699, ENST00000966700, ENST00000966701

RefSeq mRNA: 2 — MANE Select: NM_002858 NM_001122674, NM_002858

CCDS: CCDS44175, CCDS749

Canonical transcript exons

ENST00000370214 — 23 exons

Exon	Start	End
ENSE00000777384	94480464	94480606
ENSE00000777386	94478259	94478315
ENSE00000777388	94475614	94475737
ENSE00001452083	94517052	94518663
ENSE00003476085	94498602	94498679
ENSE00003509270	94491184	94491247
ENSE00003514620	94487892	94487983
ENSE00003519233	94487694	94487791
ENSE00003522194	94467919	94468007
ENSE00003532893	94464775	94464873
ENSE00003534105	94498945	94499034
ENSE00003537728	94515146	94515202
ENSE00003547386	94499495	94499614
ENSE00003554975	94489725	94489816
ENSE00003590755	94498783	94498848
ENSE00003592097	94475143	94475240
ENSE00003594138	94487542	94487611
ENSE00003607006	94489903	94489975
ENSE00003641889	94506538	94506642
ENSE00003652542	94473766	94473835
ENSE00003679024	94483170	94483239
ENSE00003688968	94458607	94458643
ENSE00003849870	94418389	94418588

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9162 / max 223.8749, expressed in 1798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4090	14.2551	1791
4091	2.9282	1342
4092	0.7329	425

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.52	gold quality
jejunal mucosa	UBERON:0000399	98.76	gold quality
epithelium of nasopharynx	UBERON:0001951	98.50	gold quality
choroid plexus epithelium	UBERON:0003911	98.26	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.19	gold quality
oocyte	CL:0000023	98.14	gold quality
esophagus squamous epithelium	UBERON:0006920	97.97	gold quality
bronchial epithelial cell	CL:0002328	97.92	gold quality
nephron tubule	UBERON:0001231	97.84	gold quality
pigmented layer of retina	UBERON:0001782	97.78	gold quality
palpebral conjunctiva	UBERON:0001812	97.61	gold quality
upper leg skin	UBERON:0004262	97.38	gold quality
caput epididymis	UBERON:0004358	97.37	gold quality
renal medulla	UBERON:0000362	97.32	gold quality
epithelium of bronchus	UBERON:0002031	97.32	gold quality
jejunum	UBERON:0002115	97.26	gold quality
bronchus	UBERON:0002185	97.19	gold quality
nasal cavity epithelium	UBERON:0005384	97.18	gold quality
colonic mucosa	UBERON:0000317	96.89	gold quality
epithelium of esophagus	UBERON:0001976	96.89	gold quality
ventricular zone	UBERON:0003053	96.81	gold quality
tongue squamous epithelium	UBERON:0006919	96.78	gold quality
trigeminal ganglion	UBERON:0001675	96.77	gold quality
duodenum	UBERON:0002114	96.59	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.59	gold quality
heart right ventricle	UBERON:0002080	96.57	gold quality
seminal vesicle	UBERON:0000998	96.44	gold quality
visceral pleura	UBERON:0002401	96.44	gold quality
mammalian vulva	UBERON:0000997	96.39	gold quality
oral cavity	UBERON:0000167	96.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.62
E-HCAD-31	no	2.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR0B1

miRNA regulators (miRDB)

148 targeting ABCD3, 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-1252-5P	100.00	69.80	2774
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 16)

• ALDP interacts with PMP70. This interaction occurs via the C-terminus of ALDP [361-745] and the C-terminus of PMP70 [338-659]. ALDP mutations P484R and R591Q abolish the interaction. (PMID:10551832)
• ALDRP interacts with PMP70. This interaction occurs via the ALDRP C-terminus [374-740] and the PMP70 C-terminus [338-659]. This interaction was demonstrated using human PMP70 and mouse ALDRP. (PMID:10551832)
• PMP70 (ABCD3) homodimerizes via the carboxy terminal half [338-659]. (PMID:10551832)
• MP70 (ABCD3) interacts with both farnesylated wild-type and farnesylation-deficient mutant PEX19. (PMID:10777694)
• MP70 interacts with PEX19 splice variants PEX19-delta-E2 and PEX19p-delta-E8. (PMID:11883941)
• Pex19p binds to PMP70 co-translationally and keeps PMP70 in a proper conformation for the localization to peroxisome. (PMID:16344115)
• Testosterone metabolites did not alter expression of ABCD3 mRNA in fibroblasts from X-linked adrenoleukodystrophy patients. (PMID:17602313)
• investigation of organelle-targeting properties of N-terminal portions of peroxisomal PMP70; amino acid sequence and domain structure of human form discussed (PMID:20007743)
• We postulate a role for human ABCD3 in the oxidation of dicarboxylic acids and a role in buffering fatty acids that are overflowing from the mitochondrial beta-oxidation system (PMID:24333844)
• Deficiency of peroxisomal ABCD3 resulted in bile acid biosynthesis defect. (PMID:25168382)
• Increased ABCD3 expression correlates with Gleason Score. (PMID:25802834)
• The N-terminal motif of PMP70 suppresses cotranslational targeting to the endoplasmic reticulum. (PMID:26711236)
• Data show that ACBD3 can recruit PI4KB to model membranes as well as redirect PI4KB to cellular membranes where it is not naturally found. Also, results show that ACBD3 regulates the enzymatic activity of PI4KB kinase through membrane recruitment rather than allostery. (PMID:27009356)
• ABCD1 and ABCD2 are involved in the transport of long and very long chain fatty acids (VLCFA) or their CoA-derivatives into peroxisomes with different substrate specificities, while ABCD3 is involved in the transport of branched chain acyl-CoA into peroxisomes.ABCD4 is deduced to take part in the transport of vitamin B12 from lysosomes into the cytosol. (PMID:27766264)
• In HEK293 cells, the D-bifunctional protein (HSD17B4) and the peroxisomal ABC transporter ABCD3 are essential in peroxisomal oxidation of lauric and palmitic acid. (PMID:30540494)
• Peroxisomal ABC Transporters: An Update. (PMID:34198763)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcd3b	ENSDARG00000002947
danio_rerio	abcd3a	ENSDARG00000104085
mus_musculus	Abcd3	ENSMUSG00000028127
rattus_norvegicus	Abcd3	ENSRNOG00000011929
drosophila_melanogaster	Abcd3	FBGN0031069
caenorhabditis_elegans		WBGENE00004058
caenorhabditis_elegans		WBGENE00004059

Paralogs (3): ABCD1 (ENSG00000101986), ABCD4 (ENSG00000119688), ABCD2 (ENSG00000173208)

Protein

Protein identifiers

ATP-binding cassette sub-family D member 3 — P28288 (reviewed: P28288)

Alternative names: 70 kDa peroxisomal membrane protein

All UniProt accessions (2): A0A3B3ITW3, P28288

UniProt curated annotations — full annotation on UniProt →

Function. Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that catalyzes the transport of long-chain fatty acids (LCFA)-CoA, dicarboxylic acids-CoA, long-branched-chain fatty acids-CoA and bile acids from the cytosol to the peroxisome lumen for beta-oxydation. Has fatty acyl-CoA thioesterase and ATPase activities. Probably hydrolyzes fatty acyl-CoAs into free fatty acids prior to their ATP-dependent transport into peroxisomes. Thus, play a role in regulation of LCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation.

Subunit / interactions. Homodimers. Can form heterodimers with ABCD1 and ABCD2. Dimerization is necessary to form an active transporter. Interacts with PEX19; mediates the targeting of ABCD3 to peroxisomes.

Subcellular location. Peroxisome membrane.

Post-translational modifications. Ubiquitinated by PEX2 during pexophagy in response to starvation, leading to its degradation.

Disease relevance. Congenital bile acid synthesis defect 5 (CBAS5) [MIM:616278] An autosomal recessive disorder characterized by hepatosplenomegaly, hepatic fibrosis, progressive liver failure, and accumulation of peroxisomal C27-bile acid intermediates in plasma. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ABC transporter superfamily. ABCD family. Peroxisomal fatty acyl CoA transporter (TC 3.A.1.203) subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P28288-1	1	yes
P28288-2	2
P28288-3	3

RefSeq proteins (2): NP_001116146, NP_002849* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR005283	FA_transporter	Family
IPR011527	ABC1_TM_dom	Domain
IPR017871	ABC_transporter-like_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036640	ABC1_TM_sf	Homologous_superfamily
IPR050835	ABC_transporter_sub-D	Family

Pfam: PF00005, PF06472

Enzyme classification (BRENDA):

• EC 7.6.2.4 — ABC-type fatty-acyl-CoA transporter (BRENDA: 8 organisms, 66 substrates, 10 inhibitors, 1 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.28	1

Catalyzed reactions (Rhea), 12 shown:

• pristanoyl-CoA + H2O = 2,6,10,14-tetramethylpentadecanoate + CoA + H(+) (RHEA:40415)
• a very long-chain fatty acyl-CoA + H2O = a very long-chain fatty acid + CoA + H(+) (RHEA:67072)
• a very long-chain fatty acid(in) + ATP + H2O = a very long-chain fatty acid(out) + ADP + phosphate + H(+) (RHEA:67080)
• a long-chain fatty acyl-CoA + H2O = a long-chain fatty acid + CoA + H(+) (RHEA:67680)
• a long-chain fatty acid(in) + ATP + H2O = a long-chain fatty acid(out) + ADP + phosphate + H(+) (RHEA:67684)
• 2,6,10,14-tetramethylpentadecanoate(in) + ATP + H2O = 2,6,10,14-tetramethylpentadecanoate(out) + ADP + phosphate + H(+) (RHEA:67688)
• hexadecanedioate(in) + ATP + H2O = hexadecanedioate(out) + ADP + phosphate + H(+) (RHEA:67692)
• hexadecanedioyl-CoA + H2O = hexadecanedioate + CoA + H(+) (RHEA:67696)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA + H2O = (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + CoA + H(+) (RHEA:67700)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate(in) + ATP + H2O = (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate(out) + ADP + phosphate + H(+) (RHEA:67704)
• (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate(in) + ATP + H2O = (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate(out) + ADP + phosphate + H(+) (RHEA:67708)
• (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA + H2O = (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + CoA + H(+) (RHEA:67712)

UniProt features (86 total): helix 27, strand 17, turn 10, sequence conflict 6, modified residue 5, mutagenesis site 5, transmembrane region 4, glycosylation site 3, splice variant 3, domain 2, chain 1, sequence variant 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9W65	ELECTRON MICROSCOPY	2.94
8Z9X	ELECTRON MICROSCOPY	2.96
9NGJ	ELECTRON MICROSCOPY	3.13
8Z0F	ELECTRON MICROSCOPY	3.27
9W62	ELECTRON MICROSCOPY	3.28
9W63	ELECTRON MICROSCOPY	3.29
9W66	ELECTRON MICROSCOPY	3.3
9NGM	ELECTRON MICROSCOPY	3.33
9W64	ELECTRON MICROSCOPY	3.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28288-F1	83.39	0.52

Functional residue map

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

Ligand- & substrate-binding residues (1): 473–480

Post-translational modifications (5): 260, 399, 533, 659, 61

Glycosylation sites (3): 12, 106, 206

Mutagenesis-validated functional residues (5):

Position	Phenotype
21–23	abolishes localization to peroxisomes.
70–71	abolishes localization to peroxisomes.
307–308	abolishes localization to peroxisomes.
478	decreased atp-binding affinity.
572	decreased atpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1369062	ABC transporters in lipid homeostasis
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9603798	Class I peroxisomal membrane protein import
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-382551	Transport of small molecules
R-HSA-382556	ABC-family protein mediated transport
R-HSA-9012999	RHO GTPase cycle
R-HSA-9609507	Protein localization
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 424 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, HORIUCHI_WTAP_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, KEGG_ABC_TRANSPORTERS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS

GO Biological Process (12): very long-chain fatty acid metabolic process (GO:0000038), fatty acid biosynthetic process (GO:0006633), fatty acid beta-oxidation (GO:0006635), bile acid biosynthetic process (GO:0006699), peroxisome organization (GO:0007031), response to xenobiotic stimulus (GO:0009410), bile acid and bile salt transport (GO:0015721), long-chain fatty acid import into peroxisome (GO:0015910), very long-chain fatty acid catabolic process (GO:0042760), phytanic acid metabolic process (GO:1903512), lipid transport (GO:0006869), transmembrane transport (GO:0055085)

GO Molecular Function (11): long-chain fatty acid transmembrane transporter activity (GO:0005324), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ATPase-coupled transmembrane transporter activity (GO:0042626), protein homodimerization activity (GO:0042803), fatty acyl-CoA hydrolase activity (GO:0047617), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), identical protein binding (GO:0042802)

GO Cellular Component (6): mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RHO GTPase cycle	2
ABC-family protein mediated transport	1
Protein localization	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Transport of small molecules	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid metabolic process	2
monocarboxylic acid biosynthetic process	2
fatty acid catabolic process	2
long-chain fatty acid transport	2
transport	2
ATP-dependent activity	2
cytoplasm	2
peroxisome	2
cellular anatomical structure	2
lipid biosynthetic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
bile acid metabolic process	1
organelle organization	1
response to chemical	1
lipid transport	1
monocarboxylic acid transport	1
organic hydroxy compound transport	1
intercellular transport	1
peroxisomal membrane transport	1
intracellular lipid transport	1
fatty acid transmembrane transport	1
very long-chain fatty acid metabolic process	1
long-chain fatty acid metabolic process	1
methyl-branched fatty acid metabolic process	1
lipid localization	1
cellular process	1
fatty acid transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
identical protein binding	1
protein dimerization activity	1
acyl-CoA hydrolase activity	1
ATPase-coupled transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1

Protein interactions and networks

STRING

1318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCD3	PEX19	P40855	908
ABCD3	PEX5	P50542	899
ABCD3	PEX16	Q9Y5Y5	881
ABCD3	PEX2	P28328	847
ABCD3	ACOX1	Q15067	801
ABCD3	ACSBG1	Q96GR2	800
ABCD3	SLC27A2	O14975	793
ABCD3	ACOX3	O15254	741
ABCD3	PEX13	Q92968	740
ABCD3	PEX11B	O96011	733
ABCD3	PEX3	P56589	727
ABCD3	TOMM20	Q15388	713
ABCD3	PEX1	O43933	698
ABCD3	ACSL3	O95573	690
ABCD3	PEX6	Q13608	689

IntAct

198 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ABCD3	PEX19	psi-mi:“MI:0407”(direct interaction)	0.680
PEX19	ABCD3	psi-mi:“MI:0915”(physical association)	0.680
PEX19	ABCD3	psi-mi:“MI:0403”(colocalization)	0.680
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
DYRK1B	BMAL1	psi-mi:“MI:0914”(association)	0.530
STOM	EI24	psi-mi:“MI:0914”(association)	0.510
ABCD1	ABCD3	psi-mi:“MI:0915”(physical association)	0.510
ABCD3	ABCD1	psi-mi:“MI:0915”(physical association)	0.510
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
vpr	AGPS	psi-mi:“MI:0914”(association)	0.460
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
LACC1	ABCD3	psi-mi:“MI:0403”(colocalization)	0.380
LACC1	ABCD3	psi-mi:“MI:2364”(proximity)	0.380
TUFT1	ABCD3	psi-mi:“MI:0915”(physical association)	0.370
ABCD3	PSMA1	psi-mi:“MI:0915”(physical association)	0.370
ABCD3	ABCD3	psi-mi:“MI:0915”(physical association)	0.370
Abcd2	ABCD3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (340): ABCD3 (Affinity Capture-RNA), ABCD3 (Affinity Capture-RNA), ABCD3 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCD3 (Affinity Capture-RNA), ABCD3 (Affinity Capture-MS), ABCD3 (Co-fractionation), EEF2 (Co-fractionation), ABCD3 (Proximity Label-MS), ABCD3 (Proximity Label-MS), ABCD3 (Proximity Label-MS), ABCD3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1LQE1, A0A0U5GNT1, A0A125QXJ1, A0A142I732, A0A179H0T5, A0A8J9WHR9, D3ZHR2, E7F6F7, F1RBC8, G4N2B5, H2LNR5, J9VQH1, O14678, O70595, O75027, O89016, P0CL92, P16970, P21441, P28288, P33897, P48410, P55096, P9WEL8, Q08D64, Q09427, Q09428, Q09429, Q2UPC0, Q4PH16, Q4WPP6, Q5AV00, Q5AV07, Q5R9Z5, Q61102, Q61285, Q66H39, Q6FIK3, Q704E8, Q751N2

Diamond homologs: A0A0U1LQE1, B2RX12, D3ZHR2, F1RBC8, O15438, O15439, O88563, P16877, P16970, P21441, P28288, P31826, P33897, P34230, P41909, P48410, P55096, P77279, P9WQI8, P9WQI9, Q1C812, Q1CJG3, Q1LKJ2, Q1QR47, Q21PQ7, Q54W19, Q57335, Q5E6M2, Q5F364, Q61285, Q66AT7, Q7CIC2, Q7JUN3, Q8T8P3, Q94FB9, Q9I3N7, Q9QY44, Q9UBJ2, Q9Z651, S8EXU2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PEX2	“up-regulates activity”	ABCD3	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 225 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Class I peroxisomal membrane protein import	5	17.7×	1e-03
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	17.7×	1e-03
Downstream signal transduction	5	12.9×	2e-03
FCERI mediated MAPK activation	5	11.8×	3e-03
RAF activation	5	11.4×	3e-03
Signaling by SCF-KIT	6	10.1×	2e-03
Signaling by RAF1 mutants	5	9.5×	4e-03
RHOF GTPase cycle	5	8.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
peroxisome organization	5	21.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	118
Likely benign	71
Benign	22

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
187846	NM_002858.4(ABCD3):c.1903-573_*1108del	Pathogenic
4540400	ABCD3, (CCG)n REPEAT EXPANSION, 5-PRIME UTR	Pathogenic

SpliceAI

3505 predictions. Top by Δscore:

Variant	Effect	Δscore
1:94418586:CGGG:C	donor_loss	1.0000
1:94418587:GG:G	donor_gain	1.0000
1:94418588:GG:G	donor_gain	1.0000
1:94418589:G:GA	donor_loss	1.0000
1:94418589:G:GG	donor_gain	1.0000
1:94418590:T:G	donor_loss	1.0000
1:94457929:G:GT	donor_gain	1.0000
1:94458605:A:AG	acceptor_gain	1.0000
1:94458606:G:GG	acceptor_gain	1.0000
1:94458640:TGAG:T	donor_loss	1.0000
1:94458642:AG:A	donor_loss	1.0000
1:94458643:GG:G	donor_loss	1.0000
1:94458644:GT:G	donor_loss	1.0000
1:94464774:GAAA:G	acceptor_gain	1.0000
1:94464870:AGAGG:A	donor_loss	1.0000
1:94464871:GAG:G	donor_gain	1.0000
1:94464872:AGG:A	donor_loss	1.0000
1:94464873:GGTA:G	donor_loss	1.0000
1:94464874:G:C	donor_loss	1.0000
1:94464875:T:A	donor_loss	1.0000
1:94473764:A:AG	acceptor_gain	1.0000
1:94473764:AGT:A	acceptor_gain	1.0000
1:94473765:G:GG	acceptor_gain	1.0000
1:94473765:GT:G	acceptor_gain	1.0000
1:94473765:GTG:G	acceptor_gain	1.0000
1:94473765:GTGGT:G	acceptor_gain	1.0000
1:94473831:CTCTT:C	donor_gain	1.0000
1:94473833:CTT:C	donor_gain	1.0000
1:94473836:G:GG	donor_gain	1.0000
1:94475137:TTTTA:T	acceptor_loss	1.0000

AlphaMissense

4310 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:94480591:G:C	R271P	1.000
1:94498640:T:A	N475K	1.000
1:94498640:T:G	N475K	1.000
1:94498642:G:A	G476D	1.000
1:94498648:G:A	G478E	1.000
1:94498648:G:T	G478V	1.000
1:94498650:A:C	K479Q	1.000
1:94498651:A:T	K479M	1.000
1:94498653:A:C	S480R	1.000
1:94498655:T:A	S480R	1.000
1:94498655:T:G	S480R	1.000
1:94498786:T:A	W490R	1.000
1:94498786:T:C	W490R	1.000
1:94498841:T:A	V508D	1.000
1:94498848:G:C	Q510H	1.000
1:94498848:G:T	Q510H	1.000
1:94499573:T:A	W567R	1.000
1:94499573:T:C	W567R	1.000
1:94499605:A:C	Q577H	1.000
1:94499605:A:T	Q577H	1.000
1:94506572:C:A	A592D	1.000
1:94506580:G:A	D595N	1.000
1:94506580:G:C	D595H	1.000
1:94506580:G:T	D595Y	1.000
1:94506581:A:C	D595A	1.000
1:94506581:A:G	D595G	1.000
1:94506581:A:T	D595V	1.000
1:94506582:T:A	D595E	1.000
1:94506582:T:G	D595E	1.000
1:94506583:G:A	E596K	1.000

dbSNP variants (sampled 300 via entrez): RS1000016176 (1:94394573 T>C), RS1000022816 (1:94479563 A>G), RS1000024196 (1:94480415 A>C), RS1000029886 (1:94388201 T>C), RS1000039359 (1:94467821 A>G), RS1000039586 (1:94430647 T>C), RS1000056386 (1:94510634 T>C), RS1000097154 (1:94469797 C>T), RS1000109253 (1:94466242 C>T), RS1000112553 (1:94432125 T>C), RS1000147964 (1:94470101 G>A), RS1000200929 (1:94384558 C>G,T), RS1000213713 (1:94505600 A>C), RS1000243406 (1:94442559 T>C), RS1000249992 (1:94391633 C>T)

Disease associations

OMIM: gene MIM:170995 | disease phenotypes: MIM:616278, MIM:621446

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital bile acid synthesis defect 5	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital bile acid synthesis defect 5	Limited	AR

Mondo (2): congenital bile acid synthesis defect 5 (MONDO:0014564), oculopharyngodistal myopathy 5 (MONDO:0980937)

Orphanet (0):

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000183	Tongue muscle weakness
HP:0000218	High palate
HP:0000301	Abnormality of facial musculature
HP:0000408	Progressive sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000952	Jaundice
HP:0001260	Dysarthria
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001395	Hepatic fibrosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001604	Vocal cord paresis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001891	Iron deficiency anemia
HP:0002015	Dysphagia
HP:0002058	Myopathic facies
HP:0002091	Restrictive ventilatory defect
HP:0002100	Recurrent aspiration pneumonia
HP:0002240	Hepatomegaly
HP:0002505	Loss of ambulation
HP:0002705	High, narrow palate
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002904	Hyperbilirubinemia

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066926 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — ABCD subfamily of peroxisomal ABC transporters

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.56	Kd	27.73	nM	CHEMBL5653589
7.54	ED50	28.85	nM	CHEMBL5653589
5.71	Kd	1942	nM	CHEMBL3752910
5.69	ED50	2021	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147768: Binding affinity to human ABCD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0277	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147768: Binding affinity to human ABCD3 incubated for 45 mins by Kinobead based pull down assay	kd	1.9425	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
Leflunomide	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Estradiol	increases expression, affects expression, affects cotreatment	2
Nickel	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
Glupearl 19S	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
triacsin C	decreases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
clothianidin	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650810	Binding	Binding affinity to human ABCD3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9X3	Ubigene HeLa ABCD3 KO	Cancer cell line	Female
CVCL_SB08	HAP1 ABCD3 (-) 1	Cancer cell line	Male
CVCL_XK94	HAP1 ABCD3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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