ABCD3

protein-coding

ATP binding cassette subfamily D member 3, the group of ATP binding cassette subfamily D|GOLD domain containing

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

PXMP1

MANE transcript

NM_002858.4

Inheritance

ClinVar variants

P:1U:124B:44

Top phenotype

Bile acid synthesis defect, congenital, 5

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr1:94,418,389-94,518,666

External References & Databases

Ensembl (ENSG00000117528)

Transcript & Mutation Effects

hg38 • Region Span ~100.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital bile acid synthesis defect 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014564

Submitter: PanelApp Australia

congenital bile acid synthesis defect 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014564

Submitter: Ambry Genetics

congenital bile acid synthesis defect 5LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014564

Submitter: Labcorp Genetics (formerly Invitae)

congenital bile acid synthesis defect 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014564

Submitter: ClinGen

The relationship between *ABCD3* and congenital bile acid synthesis defect 5 (ABCD3 congenital bile acid synthesis defect), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2022. *ABCD3* encodes an ATP-binding cassette transporter involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs (also called peroxisomal membrane protein 70, PMP70). Some of the phenotypes associated with ABCD3 congenital bile acid synthesis defect or include hepatomegaly, jaundice and increased plasma bile acid intermediates and VLCFAs. *ABCD3* was first reported in relation to autosomal recessive congenital bile acid synthesis defect in 2015. (Ferdinandusse et al, PMID: 25168382). This is the only report of a genetic defect in *ABCD3* identified in a human patient. Earlier, *ABCD3* was associated with peroxisome biogenesis as mutations were identified in the *ABCD3* gene in patients with Zellweger syndrome. However, it was later shown that a *PEX1* defect was the underlying cause of peroxisome biogenesis disorder in those patients (PMID: 25168382). Summary of Case Level Data (1 point): A homozygous deletion variant has been reported in 1 proband in 1 publication (PMID: 25168382), wherein a truncated protein product is shown to be made. The mechanism for disease is expected to be homozygous loss of function. Summary of experimental data (4 points): This gene-disease association is supported by a mouse models that recapitulate some of the human disease phenotype (PMIDs 25168382, 34564857) and protein interactions with *ABCD1* (PMID: 10551832) and PEX19 (PMID: 16344115). In summary, there is limited evidence to support the gene-disease relationship of *ABCD3* and congenital bile acid synthesis defect 5. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal GCEP on April 27, 2022. It was reevaluated on June 6, 2025 (SOP v 10). No new evidence was added and the classification did not change.

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 5AR

Manifestation: Biochemical; Craniofacial; Gastrointestinal; Neurologic

Intervention: Gastrointestinal

Rationale: Early interventions, such as with bile replacement therapy, may be beneficial, though liver transplant may be necessary

Refs: 1301993; 9199576; 10447258; 17092750; 25168382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ABCD3 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 150

not specifiedTotal: 82

ABCD3-related disorderTotal: 26

Congenital bile acid synthesis defect 5Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002858.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	39 clinvar	2 clinvar	42
missense			111 clinvar	2 clinvar	1 clinvar	114
nonsense			4 clinvar			4
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)	1 clinvar		6 clinvar			7
Total	1	0	124	41	3	169

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002858.4	RefSeq	NP_002849.1	23	MANE Select
ENST00000370214.9	Ensembl	ENSP00000359233.4	23	MANE Select
NM_001122674.2	RefSeq	NP_001116146.1	9	Standard
ENST00000315713.5	Ensembl	ENSP00000326880.5	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
ABC transporters - Homo sapiens (human)
Nuclear Receptors in Lipid Metabolism and Toxicity
ABC transporters in lipid homeostasis
Transport of small molecules

Biological Process

fatty acid biosynthetic process
fatty acid beta-oxidation
peroxisome organization
response to organic cyclic compound
peroxisomal long-chain fatty acid import

Molecular Function

long-chain fatty acid transporter activity
protein binding
ATP binding
ATPase activity
ATPase activity, coupled to transmembrane movement of substances

Cellular Component

mitochondrion
peroxisome
peroxisomal membrane
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370214
Coding exons: 23
Length: 100290
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125739
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.54	229	366	0.626	0.0000195	4292
Missense (PolyPhen)		53	139.32	0.38041		1560
Synonymous	0.821	111	123	0.906	0.00000611	1233
Loss of Function	4.75	14	50.3	0.278	0.00000312	541

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00014	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transporter involved in the transport of branched-chain fatty acids and C27 bile acids into the peroxisome; the latter function is a crucial step in bile acid biosynthesis (PubMed:25168382). The nucleotide-binding fold acts as an ATP- binding subunit with ATPase activity (PubMed:11248239). {ECO:0000269|PubMed:11248239, ECO:0000269|PubMed:25168382}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:25168382}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.297

Intolerance Scores

LoFtool: 0.115
RVIS EVS: -0.65
RVIS percentile EVS: 16.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.806

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium