ABCD4

protein-coding

ATP binding cassette subfamily D member 4, the group of ATP binding cassette subfamily D

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. The function of this peroxisomal membrane protein is unknown. However, it is speculated that it may function as a heterodimer for another peroxisomal ABC transporter and, therefore, may modify the adrenoleukodystrophy phenotype. It may also play a role in the process of peroxisome biogenesis. Alternative splicing results in several protein-coding and non-protein-coding variants. [provided by RefSeq, Jul 2017]

Previous symbols:

PXMP1L

MANE transcript

NM_005050.4

Inheritance

ClinVar variants

P:51U:179B:125

Top phenotype

Methylmalonic aciduria and homocystinuria, cblJ type

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr14:74,285,269-74,303,055

External References & Databases

Ensembl (ENSG00000119688)

Transcript & Mutation Effects

hg38 • Region Span ~17.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylmalonic acidemia with homocystinuria, type cblJSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: G2P

methylmalonic acidemia with homocystinuria, type cblJSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: Orphanet

methylmalonic acidemia with homocystinuria, type cblJSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: PanelApp Australia

methylmalonic acidemia with homocystinuria, type cblJSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: Labcorp Genetics (formerly Invitae)

methylmalonic acidemia with homocystinuria, type cblJMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: Ambry Genetics

methylmalonic acidemia with homocystinuria, type cblJMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013925

Submitter: ClinGen

*ABCD4* was first reported in relation to autosomal recessive methylmalonic acidemia with homocystinuria, type cblJ in 2012 (Coelho et al., PMID: 22922874). The primary features of this condition include elevated methylmalonic acid and total homocysteine in blood and/or urine. However, the presentation can be variable and may include hypotonia, anemia, and pigmentation abnormalities of the skin and hair. The underlying mechanism is a failure to transport cobalamin across the lysosomal membrane during uptake, leading to reduced intracellular levels of the enzyme cofactors AdoCbl and MeCbl (PMID: 20301503). Ten variants (missense, in-frame indel, frameshift) that have been reported in nine probands in eight publications (PMIDs: 41378236; 22922874; 23141461; 25234635; 28572511; 30293248; 30651581; 33729671) are included in this curation. Co-segregation with disease has not been observed. Of note, the recurrent variant c.423C>G p.(Asn141Lys) has been reported in a homozygous state in three East Asian probands, and is associated with hyperpigmentation of the skin. The mechanism of pathogenicity is biallelic loss of function. This gene-disease association is also supported by in vitro functional assays, interactions with other proteins involved in cobalamin transport, a zebrafish model, and transgenic rescue in patient cells (PMIDs: 38069516; 22922874; 27456980; 31113616; 33845046). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on September 8, 2023. This gene-disease relationship was re-evaluated on January 23, 2026. As a result of this re-evaluation, the classification did not change.

Clinical Genomic Database (CGD)

Methylmalonic aciduria and homocystinuria, cblJ typeAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Neurologic

Intervention: Allergy/Immunology/Infectious; Biochemical; Cardiovascular

Rationale: Administration of hydroxocobalamin/methylcobalamin has been described as beneficial; Due to infectious risks, administration of G-CSF has been described, and early and aggressive treatment of infections may be benefiical; Surveillance for cardiovascular manifestations may allow early management

Refs: 22922874; 23141461

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ABCD4 variants in ClinVar

6 Conditions Cataloged

Methylmalonic acidemia with homocystinuria, type cblJTotal: 358

not providedTotal: 144

Inborn genetic diseasesTotal: 92

not specifiedTotal: 57

ABCD4-related disorderTotal: 16

Cobalamin C diseaseTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005050.4. 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			5 clinvar	98 clinvar	4 clinvar	107
missense	2 clinvar	4 clinvar	166 clinvar	21 clinvar	2 clinvar	195
nonsense	5 clinvar	3 clinvar	1 clinvar			9
start loss			1 clinvar			1
frameshift	13 clinvar	11 clinvar	2 clinvar			26
splice donor/acceptor (+/-2bp)	1 clinvar	12 clinvar	4 clinvar			17
Total	21	30	179	119	6	355

Highest pathogenic variant AF is 0.000026023337

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 169 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005050.4	RefSeq	NP_005041.1	19	MANE Select
ENST00000356924.9	Ensembl	ENSP00000349396.4	19	MANE Select
NM_001353591.2	RefSeq	NP_001340520.1	18	Standard
NM_001353592.2	RefSeq	NP_001340521.1	17	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)
Cobalamin (Cbl, vitamin B12) transport and metabolism
Metabolism
Metabolism of water-soluble vitamins and cofactors

Biological Process

cobalamin metabolic process
transmembrane transport
cellular response to leukemia inhibitory factor

Molecular Function

ATP binding
ATPase activity, coupled to transmembrane movement of substances

Cellular Component

lysosomal membrane
peroxisome
peroxisomal membrane
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356924
Coding exons: 19
Length: 17634
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125748
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.169	347	356	0.975	0.0000211	3926
Missense (PolyPhen)		99	111.19	0.89039		1225
Synonymous	-0.725	162	151	1.08	0.00000942	1200
Loss of Function	2.06	25	38.9	0.643	0.00000203	408

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00016	0.00016	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in intracellular processing of vitamin B12 (cobalamin). Could play a role in the lysosomal release of vitamin B12 into the cytoplasm. {ECO:0000269|PubMed:22922874}.;

Recessive Scores

pRec: 0.153

Intolerance Scores

LoFtool: 0.152
RVIS EVS: 0.8
RVIS percentile EVS: 87.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.413

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High