ABCD2

Summary

ABCD2 (ATP binding cassette subfamily D member 2, HGNC:66) is a protein-coding gene on chromosome 12q12, encoding ATP-binding cassette sub-family D member 2 (Q9UBJ2). ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

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. The function of this peroxisomal membrane protein is unknown; however this protein is speculated to function as a dimerization partner of ABCD1 and/or other peroxisomal ABC transporters. Mutations in this gene have been observed in patients with adrenoleukodystrophy, a severe demyelinating disease. This gene has been identified as a candidate for a modifier gene, accounting for the extreme variation among adrenoleukodystrophy phenotypes. This gene is also a candidate for a complement group of Zellweger syndrome, a genetically heterogeneous disorder of peroxisomal biogenesis.

Source: NCBI Gene 225 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 89 total — 3 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 13 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.71 (unconstrained)
• MANE Select transcript: NM_005164
• Notable: 89 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:66
Approved symbol	ABCD2
Name	ATP binding cassette subfamily D member 2
Location	12q12
Locus type	gene with protein product
Status	Approved
Aliases	ALDR, ALDRP
Ensembl gene	ENSG00000173208
Ensembl biotype	protein_coding
OMIM	601081
Entrez	225

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

MANE Select: ENST00000308666

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000308666, ENST00000961977, ENST00000961978, ENST00001112147, ENST00001138446

RefSeq mRNA: 7 — MANE Select: NM_005164 NM_001412788, NM_001412789, NM_001412790, NM_001412791, NM_001412792, NM_001412793, NM_005164

CCDS: CCDS8734

Canonical transcript exons

ENST00000308666 — 10 exons

Exon	Start	End
ENSE00001182842	39573716	39573841
ENSE00001182847	39579535	39579619
ENSE00001182851	39586152	39586297
ENSE00001182856	39600571	39600716
ENSE00001182861	39603912	39604006
ENSE00001182864	39604762	39604930
ENSE00001182868	39607599	39607714
ENSE00001182872	39616988	39617168
ENSE00001182878	39550033	39554131
ENSE00001290986	39618677	39619803

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 81.40.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9513 / max 164.2476, expressed in 478 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, cortical plate, cerebellar cortex, cerebellar hemisphere, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ABCD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

13 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.0e-09	+0.46	12:39582174:T:C
Thyroid	eqtl	1.1e-08	+0.43	12:39500565:A:G
Heart Left Ventricle	eqtl	1.3e-03	+0.13	12:39618495:C:T
Heart Atrial Appendage	eqtl	2.9e-03	+0.20	12:38635137:G:T
Skin Sun Exposed Lower leg	eqtl	4.7e-03	+0.26	12:39561937:T:C
Lung	eqtl	4.9e-03	-0.20	12:39595370:A:C
Spleen	eqtl	8.4e-03	-0.22	12:39353452:A:T
Whole Blood	eqtl	9.5e-03	-0.11	12:39603645:C:G
Colon Sigmoid	eqtl	1.4e-02	-0.63	12:39368327:C:T
Esophagus Muscularis	eqtl	3.5e-02	-0.45	12:39368327:C:T
Nerve Tibial	eqtl	3.5e-02	+0.13	12:40430424:AAGAT:A
Skin Not Sun Exposed Suprapubic	eqtl	4.7e-02	-0.51	12:39600317:A:C
Brain Cerebellar Hemisphere	eqtl	4.9e-02	+0.23	12:38910710:C:T

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
130457	4.3676	460
130458	0.4802	123
130456	0.0639	38
130455	0.0396	12

Top tissues by expression

showing 100 of 279 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.40	gold quality
cortical plate	UBERON:0005343	77.89	gold quality
cerebellar cortex	UBERON:0002129	73.81	gold quality
cerebellar hemisphere	UBERON:0002245	73.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.97	gold quality
ganglionic eminence	UBERON:0004023	71.97	gold quality
ventricular zone	UBERON:0003053	71.91	gold quality
calcaneal tendon	UBERON:0003701	71.77	gold quality
cerebellum	UBERON:0002037	71.36	gold quality
prefrontal cortex	UBERON:0000451	71.11	gold quality
right atrium auricular region	UBERON:0006631	70.11	gold quality
adipose tissue	UBERON:0001013	70.05	gold quality
subcutaneous adipose tissue	UBERON:0002190	69.46	gold quality
connective tissue	UBERON:0002384	68.96	gold quality
Brodmann (1909) area 9	UBERON:0013540	68.54	gold quality
cardiac atrium	UBERON:0002081	68.40	gold quality
omental fat pad	UBERON:0010414	68.17	gold quality
peritoneum	UBERON:0002358	68.10	gold quality
right frontal lobe	UBERON:0002810	68.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.90	gold quality
smooth muscle tissue	UBERON:0001135	67.74	gold quality
cingulate cortex	UBERON:0003027	67.12	gold quality
anterior cingulate cortex	UBERON:0009835	66.82	gold quality
putamen	UBERON:0001874	66.80	gold quality
granulocyte	CL:0000094	66.73	gold quality
caudate nucleus	UBERON:0001873	66.61	gold quality
lymph node	UBERON:0000029	66.25	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	66.20	gold quality
neocortex	UBERON:0001950	65.55	gold quality
frontal cortex	UBERON:0001870	65.33	gold quality
heart left ventricle	UBERON:0002084	65.32	gold quality
amygdala	UBERON:0001876	64.87	gold quality
cardiac ventricle	UBERON:0002082	64.50	gold quality
colonic epithelium	UBERON:0000397	64.13	gold quality
nucleus accumbens	UBERON:0001882	63.86	gold quality
right uterine tube	UBERON:0001302	63.39	gold quality
heart	UBERON:0000948	63.36	gold quality
vermiform appendix	UBERON:0001154	63.21	gold quality
endocervix	UBERON:0000458	62.77	gold quality
embryo	UBERON:0000922	62.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	62.36	gold quality
telencephalon	UBERON:0001893	62.29	gold quality
ectocervix	UBERON:0012249	62.17	gold quality
cerebral cortex	UBERON:0000956	62.05	gold quality
brain	UBERON:0000955	61.81	gold quality
hypothalamus	UBERON:0001898	61.65	gold quality
central nervous system	UBERON:0001017	61.57	gold quality
apex of heart	UBERON:0002098	61.54	gold quality
forebrain	UBERON:0001890	61.12	gold quality
bone marrow cell	CL:0002092	60.55	silver quality
tendon	UBERON:0000043	59.86	gold quality
caecum	UBERON:0001153	59.67	gold quality
body of uterus	UBERON:0009853	59.15	gold quality
rectum	UBERON:0001052	58.94	gold quality
corpus callosum	UBERON:0002336	58.52	gold quality
substantia nigra	UBERON:0002038	57.89	gold quality
uterine cervix	UBERON:0000002	57.42	gold quality
primary visual cortex	UBERON:0002436	57.29	gold quality
tonsil	UBERON:0002372	57.16	gold quality
left adrenal gland	UBERON:0001234	57.04	gold quality
gall bladder	UBERON:0002110	56.76	gold quality
decidua	UBERON:0002450	56.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	56.13	gold quality
adrenal gland	UBERON:0002369	56.10	gold quality
midbrain	UBERON:0001891	56.01	gold quality
left adrenal gland cortex	UBERON:0035825	55.99	gold quality
buccal mucosa cell	CL:0002336	55.69	gold quality
temporal lobe	UBERON:0001871	55.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	55.56	gold quality
right adrenal gland cortex	UBERON:0035827	55.10	gold quality
Ammon’s horn	UBERON:0001954	54.77	gold quality
adrenal cortex	UBERON:0001235	54.71	gold quality
fallopian tube	UBERON:0003889	54.43	gold quality
blood	UBERON:0000178	54.19	gold quality
left uterine tube	UBERON:0001303	54.16	gold quality
spinal cord	UBERON:0002240	54.14	gold quality
right adrenal gland	UBERON:0001233	54.12	gold quality
urinary bladder	UBERON:0001255	53.27	gold quality
tibial nerve	UBERON:0001323	53.23	gold quality
occipital lobe	UBERON:0002021	53.10	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
myometrium	UBERON:0001296	52.39	gold quality
uterus	UBERON:0000995	52.06	gold quality
adenohypophysis	UBERON:0002196	52.06	gold quality
left coronary artery	UBERON:0001626	51.69	gold quality
nasal cavity mucosa	UBERON:0001826	51.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	51.46	gold quality
vagina	UBERON:0000996	51.30	gold quality
multicellular organism	UBERON:0000468	51.24	gold quality
material anatomical entity	UBERON:0000465	51.23	gold quality
spleen	UBERON:0002106	51.04	gold quality
anatomical system	UBERON:0000467	50.82	gold quality
lower esophagus	UBERON:0013473	50.65	gold quality
mucosa of stomach	UBERON:0001199	50.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	50.62	gold quality
thoracic mammary gland	UBERON:0005200	50.60	gold quality
pancreatic ductal cell	CL:0002079	50.58	silver quality
mammary gland	UBERON:0001911	50.43	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.91

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 73 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Frontal cortex	tissue	21.7
Caudate putamen	tissue	20.0
Putamen	tissue	16.8
Hippocampal formation	tissue	15.5
Entorhinal cortex	tissue	15.5
Cerebral cortex	tissue	15.4
Motor cortex	tissue	15.4
Postcentral gyrus	tissue	15.0
Adipose tissue	tissue	14.8
Occipital cortex	tissue	14.6
Somatosensory cortex	tissue	14.2
Prefrontal cortex	tissue	14.1
Thalamus	tissue	13.7
Retrosplenial and cingulate cortex	tissue	13.7
Retrosplenial cortex	tissue	13.5
Temporal cortex	tissue	13.3
Insular cortex	tissue	13.3
Amygdala	tissue	12.4
Superior colliculi	tissue	12.1
Midbrain	tissue	11.7
Pons	tissue	11.4
Basal ganglia	tissue	11.1
Ventral forebrain	tissue	10.7
Periaqueductal gray	tissue	10.4
Medulla oblongata	tissue	9.5
Substantia nigra	tissue	9.1
Hypothalamus	tissue	8.3
Spinal cord	tissue	8.2
Septum	tissue	8.2
Locus coeruleus	tissue	7.3
Nucleus accumbens	tissue	6.1
Hippocampus	tissue	6.1
Retina	tissue	5.5
Cerebellum	tissue	5.3
Cervix	tissue	5.0
Olfactory bulb	tissue	4.9
Corpus callosum	tissue	4.2
Heart muscle	tissue	4.0
Lymph node	tissue	2.6
Salivary gland	tissue	2.5
Endometrium 1	tissue	2.5
Fallopian tube	tissue	2.5
Smooth muscle	tissue	2.4
Choroid plexus	tissue	2.1
Adrenal gland	tissue	1.6
Appendix	tissue	1.6
Spleen	tissue	1.5
Tonsil	tissue	1.5
Thymus	tissue	1.3
Urinary bladder	tissue	0.8
Small intestine	tissue	0.7
Breast	tissue	0.6
Stomach 1	tissue	0.6
Vagina	tissue	0.6
Rectum	tissue	0.6
Colon	tissue	0.6
Pituitary gland	tissue	0.5
Seminal vesicle	tissue	0.5
Lung	tissue	0.5
Duodenum	tissue	0.5

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Cerebellar cortex (22.7), Vermis (20.4), Flocculonodular lobe (20.1), Precentral gyrus, middle (12.3), Subiculum (11.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR0B1, NR1H3, PPARA, SREBF1, TCF7L2, THRA

miRNA regulators (miRDB)

Targeting ABCD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 138 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
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-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421

Functional genomics

gnomAD constraint: pLI 7.75e-05, LOEUF 0.714, missense Z 2.31 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000308666 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:39,553,915–39,604,006	289 / 328.8	0.88	no
12:39,604,762–39,618,968	195 / 300.2	0.65	no
12:39,618,969–39,619,615	245 / 261.2	0.94	no

Literature-anchored findings (GeneRIF, showing 16)

• ALDP and ALDRP interact via their carboxy termini. ALDP mutations P484R and R591Q abolish this interaction. This interaction was demonstrated using human ALDP and murine ALDRP. (PMID:10551832)
• ALDRP (ABCD2) homodimerizes via the C terminal half. This interaction is modelled on the demonstrated homodimerization of murine ALDRP (ABCD2). (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)
• LDRP (ABCD2) interacts with both farnesylated wild-type and farnesylation-deficient mutant PEX19. This interaction is mediated by amino acids 1-218 of ALDRP. (PMID:10777694)
• ALDRP interacts with PEX19 splice variants PEX19-delta-E2 and PEX19-delta-E8. (PMID:11883941)
• LXRalpha is a negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXRalpha binding sites (PMID:16249184)
• Testosterone metabolites increased expression of ABCD2 mRNA in fibroblasts from X-linked adrenoleukodystrophy patients. (PMID:17602313)
• These findings are of particular importance for the attempt of pharmacological induction of ABCD2 as a possible therapeutic approach in X-linked adrenoleukodystrophy. (PMID:18834860)
• HsABCD1 and HsABCD2 have distinct substrate specificities (PMID:21145416)
• The transcriptional activity of the ABCD2 promoter was strongly increased by ectopic expression of beta-catenin and TCF-4. (PMID:23437103)
• results show that although patients with ABCD2 score greater than 4 were more likely to develop recurrent TIA/CVA in short term, those with lesser score still harbour a considerable risk for TIA/CVA (PMID:24338191)
• 13-cis-retinoic acid induces ABCD2 expression in human monocytes/macrophages. (PMID:25079382)
• ABCD2 has a role, but not a strong one, in risk of early recurrent events after transient ischemic attack (PMID:25604068)
• 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)
• The functional integrity of ABCD2 may play an important role in OA pathogenesis via the accumulation of VLCFAs and stimulation of apoptotic death through altering profiles of miRNAs that target ACSL4. (PMID:30264402)
• Peroxisomal ABC Transporters: An Update. (PMID:34198763)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcd2	ENSDARG00000059409
		ENSDARG00000099178
mus_musculus	Abcd2	ENSMUSG00000055782
rattus_norvegicus	Abcd2	ENSRNOG00000015538
drosophila_melanogaster	Abcd1	FBGN0039890
caenorhabditis_elegans		WBGENE00004061

Paralogs (3): ABCD1 (ENSG00000101986), ABCD3 (ENSG00000117528), ABCD4 (ENSG00000119688)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1349467) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 23 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased fatty acids level	2
axon degeneration	2
abnormal microglial cell morphology	1
tremors	1
abnormal cerebellar Purkinje cell layer	1
Purkinje cell degeneration	1
abnormal Purkinje cell morphology	1
abnormal CNS glial cell morphology	1
abnormal dorsal root ganglion morphology	1
abnormal locomotor behavior	1
ataxia	1
hyperactivity	1
impaired coordination	1
abnormal posture	1
abnormal motor coordination/balance	1
impaired balance	1
abnormal astrocyte morphology	1
gliosis	1
abnormal nervous system electrophysiology	1
neuron degeneration	1
astrocytosis	1
abnormal nervous system physiology	1
abnormal axon morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Saccharomyces cerevisiae S288C	P41909	40.3%	Diamond
Haemophilus influenzae Rd KW20	P45221	40.2%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	Q55774	39.4%	Diamond
Dictyostelium discoideum	Q8T8P3	38.8%	Diamond
Arabidopsis thaliana	Q94FB9	37.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC02471	ncRNA	105369734
LRRK2-DT	ncRNA	107984474
SLC2A13	protein-coding	114134
REDIC1	protein-coding	283461
LINC02406	ncRNA	105369730
KIF21A	protein-coding	55605

Protein

Protein identifiers

ATP-binding cassette sub-family D member 2 — Q9UBJ2 (reviewed: Q9UBJ2)

Alternative names: Adrenoleukodystrophy-like 1, Adrenoleukodystrophy-related protein

All UniProt accessions (1): Q9UBJ2

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen. Like ABCD1 seems to have fatty acyl-CoA thioesterase (ACOT) and ATPase activities, according to this model, VLCFA-CoA as free VLCFA is transported in an ATP-dependent manner into peroxisomes after the hydrolysis of VLCFA-CoA mediated by the ACOT activity of ABCD2. Shows overlapping substrate specificities with ABCD1 toward saturated fatty acids (FA) and monounsaturated FA (MUFA) but has a distinct substrate preference for shorter VLCFA (C22:0) and polyunsaturated fatty acid (PUFA) such as C22:6-CoA and C24:6-CoA (in vitro). Thus, may play a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation.

Subunit / interactions. Homodimers. Homotetramers. The minimal functional unit is a homodimer but the major oligomeric form in peroxisomal membrane is a homotetramer. Forms heterodimers with ABCD1. Forms heterodimers with ABCD3. In addition to tetramers, some larger molecular assemblies are also found but represented only a minor fraction. Interacts with PEX19; facilitates ABCD2 insertion into the peroxisome membrane.

Subcellular location. Peroxisome membrane.

Tissue specificity. Predominantly expressed in brain and heart.

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

RefSeq proteins (7): NP_001399717, NP_001399718, NP_001399719, NP_001399720, NP_001399721, NP_001399722, NP_005155* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
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)

• 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)

UniProt features (13 total): transmembrane region 4, glycosylation site 2, domain 2, chain 1, sequence variant 1, sequence conflict 1, region of interest 1, binding site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBJ2-F1	81.65	0.45

Human Protein Atlas

Protein class: Metabolic proteins, Transporters, Primary Active Transporters, Predicted membrane proteins

Protein evidence: Evidence at protein level

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)

Position	Role
511–518	ATP

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	227, 190

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-1369062	ABC transporters in lipid homeostasis	curated
R-HSA-9603798	Class I peroxisomal membrane protein import	curated
R-HSA-382556	ABC-family protein mediated transport	—
R-HSA-9609507	Protein localization	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 266 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_PLASMA_MEMBRANE_ORGANIZATION, chr12q12, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, TAL1ALPHAE47_01, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, KEGG_ABC_TRANSPORTERS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_FATTY_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (14): very long-chain fatty acid metabolic process (GO:0000038), fatty acid biosynthetic process (GO:0006633), fatty acid beta-oxidation (GO:0006635), peroxisome organization (GO:0007031), long-chain fatty acid import into peroxisome (GO:0015910), positive regulation of fatty acid beta-oxidation (GO:0032000), very long-chain fatty acid catabolic process (GO:0042760), myelin maintenance (GO:0043217), negative regulation of cytokine production involved in inflammatory response (GO:1900016), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), neuron projection maintenance (GO:1990535), positive regulation of unsaturated fatty acid biosynthetic process (GO:2001280), regulation of fatty acid metabolic process (GO:0019217), 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), protein heterodimerization activity (GO:0046982), 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)

GO Cellular Component (4): peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

3 top-level categories:

Category	Pathways
ABC-family protein mediated transport	1
Protein localization	1
Transport of small molecules	1

GO top-level categories

55 GO namespaces:

Category	Terms
fatty acid metabolic process	3
fatty acid catabolic process	2
long-chain fatty acid transport	2
ATP-dependent activity	2
protein dimerization activity	2
cellular anatomical structure	2
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
organelle organization	1
peroxisomal membrane transport	1
intracellular lipid transport	1
fatty acid transmembrane transport	1
fatty acid beta-oxidation	1
regulation of fatty acid beta-oxidation	1
positive regulation of fatty acid oxidation	1
positive regulation of lipid catabolic process	1
very long-chain fatty acid metabolic process	1
plasma membrane organization	1
myelination	1
negative regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
negative regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species biosynthetic process	1
negative regulation of reactive oxygen species metabolic process	1
neuron projection organization	1
unsaturated fatty acid biosynthetic process	1
positive regulation of fatty acid biosynthetic process	1
regulation of unsaturated fatty acid biosynthetic process	1
regulation of ketone metabolic process	1
regulation of lipid metabolic process	1
regulation of small molecule metabolic process	1
transport	1
cellular process	1
fatty acid transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
ribonucleoside triphosphate phosphatase activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
identical protein binding	1
acyl-CoA hydrolase activity	1
ATPase-coupled transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
microbody	1
peroxisome	1
microbody membrane	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
fatty acid beta-oxidation	BP	genetic interaction
positive regulation of fatty acid beta-oxidation	BP	direct assay
very long-chain fatty acid catabolic process	BP	genetic interaction
very long-chain fatty acid metabolic process	BP	direct assay
peroxisome	CC	direct assay
ATP hydrolysis activity	MF	direct assay
ATPase-coupled transmembrane transporter activity	MF	direct assay
fatty acyl-CoA hydrolase activity	MF	direct assay
protein homodimerization activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 406 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCD2	ACSBG1	Q96GR2	845
ABCD2	SLC27A2	O14975	798
ABCD2	PLXNB3	Q9ULL4	714
ABCD2	BCAP31	P51572	663
ABCD2	ELOVL1	Q9BW60	533
ABCD2	ACSL3	O95573	518
ABCD2	PEX7	O00628	517
ABCD2	ACSL6	Q9UKU0	505
ABCD2	ACSL4	O60488	499
ABCD2	AKR1B1	P15121	493
ABCD2	L1CAM	P32004	490
ABCD2	PEX19	P40855	469
ABCD2	PEX11A	O75192	466
ABCD2	ACSL1	P33121	462
ABCD2	PEX11B	O96011	455

IntAct

Human interaction partners of ABCD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
PEX19	direct interaction	0.440	1
ABCD1	physical association	0.370	1

BioGRID (12 interactions; top human partners by supporting records): PEX19 (Reconstituted Complex; 4 records), ABCD1 (Two-hybrid), FIS1 (FRET), HAO2 (FRET), NTRK1 (Affinity Capture-MS), PARP16 (Proximity Label-MS), PEX5 (FRET)

Disease & clinical

Genetic variants

Variant evidence for ABCD2: 89 ClinVar records (4 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	74
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
221992	GRCh37/hg19 12p11.21-q13.12(chr12:31886971-50360461)x3	Pathogenic	criteria provided, single submitter	1
1527702	GRCh37/hg19 12q11-13.12(chr12:37857750-49791459)x3	Pathogenic	criteria provided, single submitter	1
687619	GRCh37/hg19 12q12(chr12:39577315-40582797)x1	Pathogenic	no assertion criteria provided	1
443519	GRCh37/hg19 12p11.22-q12(chr12:29123400-40956186)x3	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ABCD2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,056):

Position(s)	Effect	Δscore	Sites
12:39553925	donor_gain	1.0000
12:39600717–39600718	acceptor_loss	1.0000	4
12:39604007–39604008	acceptor_loss	1.0000	3
12:39604013	acceptor_gain	1.0000
12:39604760–39604761	donor_loss	1.0000	5
12:39604803	donor_gain	1.0000
12:39604931–39604932	acceptor_loss	1.0000	5
12:39604939	acceptor_gain	1.0000
12:39607597–39607598	donor_loss	1.0000	5
12:39607715–39607716	acceptor_loss	1.0000	6

AlphaMissense

2,144 missense substitutions predicted likely pathogenic (of 4,847 scored), across 520 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D633	8	0.999	1.000
D234	8	0.996	0.998
D213	8	0.991	0.998
H671	8	0.991	0.998
H663	8	0.980	0.997
D200	8	0.971	0.992
F521	8	0.970	0.991
F278	8	0.969	0.998
S637	8	0.957	0.999
F143	8	0.956	0.994
N161	8	0.955	0.998
N513	8	0.953	0.999
D128	8	0.950	0.992
D207	8	0.944	0.984
F308	8	0.940	0.987
H296	8	0.936	0.993
S640	8	0.933	0.999
F389	8	0.929	0.993
D642	8	0.927	0.976
F217	8	0.925	0.993

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Glioblastoma Multiforme)

Disease associations

OMIM: gene MIM:601081 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs4284427			Allele C is associated with decreased expression of ABCD2 in HapMap cells.	PMID:21383772

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — ABCD subfamily of peroxisomal ABC transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	2
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	decreases expression	1
tobacco tar	decreases expression, decreases reaction	1
allyl sulfide	decreases reaction, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
clothianidin	decreases expression	1
bisphenol S	increases expression	1
Docetaxel	decreases response to substance, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Endosulfan	decreases reaction, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	affects expression	1
Asbestos, Crocidolite	decreases expression	1
Silver Compounds	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.