ABCD4

Summary

ABCD4 (ATP binding cassette subfamily D member 4, HGNC:68) is a protein-coding gene on chromosome 14q24.3, encoding Lysosomal cobalamin transporter ABCD4 (O14678). Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner.

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.

Source: NCBI Gene 5826 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonic acidemia with homocystinuria, type cblJ (Strong, GenCC)
• Clinical variants (ClinVar): 575 total — 24 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_005050

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:68
Approved symbol	ABCD4
Name	ATP binding cassette subfamily D member 4
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	PMP69, P70R, EST352188
Ensembl gene	ENSG00000119688
Ensembl biotype	protein_coding
OMIM	603214
Entrez	5826

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 30 protein_coding, 12 nonsense_mediated_decay, 9 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000356924, ENST00000460308, ENST00000465085, ENST00000466822, ENST00000469672, ENST00000470637, ENST00000474270, ENST00000475240, ENST00000477803, ENST00000481348, ENST00000481935, ENST00000484380, ENST00000489207, ENST00000489678, ENST00000493427, ENST00000493752, ENST00000496015, ENST00000553486, ENST00000553745, ENST00000553998, ENST00000554453, ENST00000555617, ENST00000555904, ENST00000556119, ENST00000556517, ENST00000556971, ENST00000557554, ENST00000557588, ENST00000885451, ENST00000885452, ENST00000885453, ENST00000885454, ENST00000885455, ENST00000885456, ENST00000885457, ENST00000885458, ENST00000885459, ENST00000885460, ENST00000934325, ENST00000934326, ENST00000934327, ENST00000934328, ENST00000934329, ENST00000934330, ENST00000934331, ENST00000934332, ENST00000934333, ENST00000934334, ENST00000934335, ENST00000948604, ENST00000948605, ENST00000948606, ENST00000948607

RefSeq mRNA: 23 — MANE Select: NM_005050 NM_001353591, NM_001353592, NM_001353593, NM_001353594, NM_001353595, NM_001353596, NM_001353597, NM_001353598, NM_001353599, NM_001353600, NM_001353601, NM_001353602, NM_001353603, NM_001353604, NM_001353605, NM_001353606, NM_001353607, NM_001353608, NM_001353609, NM_001353610, NM_005050, NM_020324, NM_020325

CCDS: CCDS9828

Canonical transcript exons

ENST00000356924 — 19 exons

Exon	Start	End
ENSE00001737357	74285269	74286529
ENSE00001919424	74302875	74302934
ENSE00003467878	74290291	74290499
ENSE00003472805	74292748	74292869
ENSE00003482209	74299548	74299675
ENSE00003504695	74289483	74289519
ENSE00003521598	74288207	74288259
ENSE00003524734	74292287	74292376
ENSE00003532599	74296333	74296449
ENSE00003542422	74286701	74286816
ENSE00003562324	74300150	74300268
ENSE00003586260	74288716	74288765
ENSE00003606824	74290027	74290118
ENSE00003618875	74287810	74287886
ENSE00003627439	74293154	74293248
ENSE00003632399	74292551	74292642
ENSE00003633332	74297930	74298069
ENSE00003646447	74295854	74295979
ENSE00003648817	74295148	74295198

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.2537 / max 178.7572, expressed in 1809 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144016	13.3086	1802
144015	8.4960	1701
144017	0.4491	220

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.01	gold quality
right ovary	UBERON:0002118	96.75	gold quality
cerebellar hemisphere	UBERON:0002245	96.73	gold quality
left ovary	UBERON:0002119	96.67	gold quality
cerebellar cortex	UBERON:0002129	96.52	gold quality
right lobe of thyroid gland	UBERON:0001119	96.40	gold quality
endocervix	UBERON:0000458	96.25	gold quality
body of uterus	UBERON:0009853	96.16	gold quality
tibial nerve	UBERON:0001323	96.00	gold quality
left lobe of thyroid gland	UBERON:0001120	95.97	gold quality
metanephros cortex	UBERON:0010533	95.97	gold quality
ventricular zone	UBERON:0003053	95.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.60	gold quality
ganglionic eminence	UBERON:0004023	95.52	gold quality
ectocervix	UBERON:0012249	95.44	gold quality
adenohypophysis	UBERON:0002196	95.27	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.19	gold quality
apex of heart	UBERON:0002098	95.08	gold quality
thyroid gland	UBERON:0002046	95.03	gold quality
omental fat pad	UBERON:0010414	95.00	gold quality
peritoneum	UBERON:0002358	94.97	gold quality
mucosa of stomach	UBERON:0001199	94.84	gold quality
pituitary gland	UBERON:0000007	94.63	gold quality
cerebellum	UBERON:0002037	94.61	gold quality
right lobe of liver	UBERON:0001114	94.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.46	gold quality
left uterine tube	UBERON:0001303	94.45	gold quality
right adrenal gland cortex	UBERON:0035827	94.45	gold quality
right adrenal gland	UBERON:0001233	94.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting ABCD4, 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-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-3123	99.47	67.15	2693

Literature-anchored findings (GeneRIF, showing 10)

• expression tends to be correlated with the severity of X-linked adrenoleukodystrophy (PMID:15800013)
• Defects in ABCB4 have been found to cause progressive familial intrahepatic cholestasis type 3. (PMID:21514256)
• mutations altering the putative ATPase domain of ABCD4 affect its function, suggesting that the ATPase activity of ABCD4 may be involved in intracellular processing of vitamin B12. (PMID:22922874)
• Results propose a model whereby membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of lysosomal vitamin B12 to cytoplasmic MMACHC. (PMID:25535791)
• endogenous ABCD4 was localized to both lysosomes and the ER, and its lysosomal localization was disturbed by knockout of LMBRD1 (PMID:27456980)
• 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)
• Data suggest that ABCD4 lysosomal targeting depends on co-expression of and interaction with LMBRD1; mutations in LMBRD1 and ABCD4 that result in cobalamin metabolism disorders cblF and cblJ (or mutations in ATPase domain) disrupt interactions between LMBRD1 and ABCD4. (LMBRD1 = nuclear export signal-interacting protein; ABCD4 = ATP-binding cassette, sub-family D (ALD), member 4) (PMID:28572511)
• Utilizing whole-exome sequencing, we found two novel MTR variants c.871C>T (p.Pro291Ser) and c.1771C>T (p.Arg591*) in Patient 1, and a ABCD4 homozygous variant c.423C>G (p.Asn141Lys) in Patient 2. Our study identified the first Cobalamin Gpatient and cobalamin J patient in mainland China, and highlighted comprehensive metabolic analyses and genetic tests in patients suspected of cobalamin defects (PMID:30651581)
• Cryo-EM structure of human lysosomal cobalamin exporter ABCD4. (PMID:31467407)
• Cobalamin J disease detected on newborn screening: Novel variant and normal neurodevelopmental course. (PMID:33729671)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcd4	ENSDARG00000061770
mus_musculus	Abcd4	ENSMUSG00000021240
rattus_norvegicus	Abcd4	ENSRNOG00000011964
caenorhabditis_elegans		WBGENE00004060
caenorhabditis_elegans		WBGENE00004062

Paralogs (3): ABCD1 (ENSG00000101986), ABCD3 (ENSG00000117528), ABCD2 (ENSG00000173208)

Protein

Protein identifiers

Lysosomal cobalamin transporter ABCD4 — O14678 (reviewed: O14678)

Alternative names: ATP-binding cassette sub-family D member 4, PMP70-related protein, Peroxisomal membrane protein 1-like, Peroxisomal membrane protein 69

All UniProt accessions (10): O14678, E9PI46, E9PPB6, G3V3W1, G3V4U7, H0YCY9, H0YJ78, H0YJ82, H0YJL8, H0YJX8

UniProt curated annotations — full annotation on UniProt →

Function. Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner. Targeted by LMBRD1 lysosomal chaperone from the endoplasmic reticulum to the lysosomal membrane. Then forms a complex with lysosomal chaperone LMBRD1 and cytosolic MMACHC to transport cobalamin across the lysosomal membrane.

Subunit / interactions. Homodimer or heterodimer. Interacts with LMBRD1; this interaction induces the translocation of ABCD4 from the ER to the lysosome membrane. Interacts with LMBRD1 and MMACHC; this interaction ensures the transport of cobalamin from the lysosome to the cytosol.

Subcellular location. Endoplasmic reticulum membrane. Lysosome membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ) [MIM:614857] A disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include feeding difficulties, poor growth, hypotonia, lethargy, anemia, and developmental delay. 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.

RefSeq proteins (23): NP_001340520, NP_001340521, NP_001340522, NP_001340523, NP_001340524, NP_001340525, NP_001340526, NP_001340527, NP_001340528, NP_001340529, NP_001340530, NP_001340531, NP_001340532, NP_001340533, NP_001340534, NP_001340535, NP_001340536, NP_001340537, NP_001340538, NP_001340539, NP_005041, NP_064720, NP_064730 (=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 7.6.2.8 — ABC-type vitamin B12 transporter (BRENDA: 12 organisms, 26 substrates, 12 inhibitors, 3 Km, 2 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	0.053–0.077	2

Catalyzed reactions (Rhea), 1 shown:

• an R-cob(III)alamin(out) + ATP + H2O = an R-cob(III)alamin(in) + ADP + phosphate + H(+) (RHEA:17873)

UniProt features (26 total): mutagenesis site 8, sequence variant 7, transmembrane region 5, sequence conflict 2, domain 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6JBJ	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14678-F1	87.18	0.60

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): 421–428

Mutagenesis-validated functional residues (8):

Position	Phenotype
141	does not affect atpase nor cobalamin transport activities.
319	decreases of atpase activity. decreases cobalamin transport activity.
319	does not affect atpase activity. does not affect cobalamin transport activity.
426	decreases interaction with lmbd1. decreases colocalization with lmbd1. decreases cobalamin transport activity.
427	loss of atpase activity. loss of cobalamin transport activity.
427	decreases interaction with lmbd1. decreases colocalization with lmbd1. decreases cobalamin transport activity. reduces s
548	decreases interaction with lmbd1. reduces synthesis of adenosylcobalamin and methylcobalamin.
549	decreases atpase activity. reduces synthesis of adenosylcobalamin and methylcobalamin.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5683329	Defective ABCD4 causes MAHCJ
R-HSA-9758881	Uptake of dietary cobalamins into enterocytes
R-HSA-9758890	Transport of RCbl within the body
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-5619084	ABC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-5668914	Diseases of metabolism

MSigDB gene sets: 285 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, KEGG_ABC_TRANSPORTERS, chr14q24, GOBP_COBALAMIN_METABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, INGRAM_SHH_TARGETS_UP

GO Biological Process (8): fatty acid beta-oxidation (GO:0006635), peroxisome organization (GO:0007031), cobalamin metabolic process (GO:0009235), cobalamin transport (GO:0015889), long-chain fatty acid import into peroxisome (GO:0015910), very long-chain fatty acid catabolic process (GO:0042760), transmembrane transport (GO:0055085), cellular response to leukemia inhibitory factor (GO:1990830)

GO Molecular Function (9): long-chain fatty acid transmembrane transporter activity (GO:0005324), ATP binding (GO:0005524), ABC-type vitamin B12 transporter activity (GO:0015420), ATP hydrolysis activity (GO:0016887), ATPase-coupled transmembrane transporter activity (GO:0042626), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), ABC-type transporter activity (GO:0140359)

GO Cellular Component (8): lysosomal membrane (GO:0005765), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), ATP-binding cassette (ABC) transporter complex (GO:0043190), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Cobalamin (Cbl, vitamin B12) transport and metabolism	2
Disease	2
Defects in cobalamin (B12) metabolism	1
ABC transporter disorders	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disorders of transmembrane transporters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid catabolic process	2
long-chain fatty acid transport	2
ATP-dependent activity	2
fatty acid ligase activity	1
fatty acid oxidation	1
organelle organization	1
tetrapyrrole metabolic process	1
vitamin transport	1
nitrogen 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
transport	1
cellular process	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
fatty acid transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cobalamin transport	1
vitamin transmembrane transporter activity	1
ABC-type transporter activity	1
ribonucleoside triphosphate phosphatase activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
ATPase-coupled transmembrane transporter activity	1
lysosome	1
lytic vacuole membrane	1
microbody	1
peroxisome	1
microbody membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1214 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCD4	ACSBG1	Q96GR2	813
ABCD4	LMBRD1	Q9NUN5	812
ABCD4	SLC27A2	O14975	748
ABCD4	MMACHC	Q9Y4U1	735
ABCD4	MMADHC	Q9H3L0	714
ABCD4	ABCF3	Q9NUQ8	666
ABCD4	VRTN	Q9H8Y1	651
ABCD4	ABCF2	Q9UG63	623
ABCD4	MMAB	Q96EY8	622
ABCD4	ABCA5	Q8WWZ7	608
ABCD4	CD320	Q9NPF0	600
ABCD4	MMUT	P22033	591
ABCD4	ABCA13	Q86UQ4	580
ABCD4	MTR	Q99707	578
ABCD4	ABCB9	Q9NP78	576

IntAct

61 interactions, top by confidence:

A	B	Type	Score
LMBRD1	ABCD4	psi-mi:“MI:2364”(proximity)	0.670
ABCD4	LMBRD1	psi-mi:“MI:0403”(colocalization)	0.670
ABCD4	LMBRD1	psi-mi:“MI:0915”(physical association)	0.670
ABCD4	ABCD4	psi-mi:“MI:0915”(physical association)	0.640
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
ABCD4	FAM234B	psi-mi:“MI:0915”(physical association)	0.620
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
FSHR	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
ABCD4	ATP5F1B	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	ABCD4	psi-mi:“MI:0915”(physical association)	0.370
FAM189B	KLRG2	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
ATP2B2	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC17A2	PSMD11	psi-mi:“MI:0914”(association)	0.350
PDGFRB	ABCD4	psi-mi:“MI:0914”(association)	0.350
PCDHA3	ABCD4	psi-mi:“MI:0914”(association)	0.350
	ABCD4	psi-mi:“MI:0914”(association)	0.350

BioGRID (52): ABCD4 (Two-hybrid), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Affinity Capture-MS), ABCD4 (Two-hybrid), XRCC6 (Two-hybrid), PEA15 (Two-hybrid), ATP5B (Proximity Label-MS), ABCD4 (Proximity Label-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: A0LM36, A0PY57, A0QFE1, O14678, O89016, P14175, P17328, Q03024, Q2FFM9, Q2G2M9, Q2YU20, Q3Z3I7, Q55774, Q5HEQ8, Q5Z0P5, Q60AA3, Q6FAN3, Q6G868, Q6GFJ1, Q73YZ5, Q7A0J1, Q7A4T3, Q7VNG4, Q83LN2, Q8NR42, Q8SQI5, Q99T13, Q9VL32, A0A179H0T5, O15438, O88563, P18767, P23596, P45081, Q5P3L0, Q71ED1, Q94FB9, A0A0D1BUH6, A1AC19, A1BE50

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	23
Uncertain significance	182
Likely benign	213
Benign	90

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069117	NM_005050.4(ABCD4):c.1294del (p.Arg432fs)	Pathogenic
1335925	NM_005050.4(ABCD4):c.1125del (p.Trp377fs)	Pathogenic
144518	GRCh38/hg38 14q24.3-32.33(chr14:73655772-106879298)x3	Pathogenic
1453520	NC_000014.8:g.(?74766231)(74769615_?)del	Pathogenic
1941455	NM_005050.4(ABCD4):c.1213_1214dup (p.Asp406fs)	Pathogenic
2141575	NM_005050.4(ABCD4):c.373del (p.Arg125fs)	Pathogenic
2684728	GRCh37/hg19 14q23.1-32.33(chr14:58894502-107227240)x3	Pathogenic
2691699	NM_005050.4(ABCD4):c.1425dup (p.Tyr476fs)	Pathogenic
2728334	NM_005050.4(ABCD4):c.1606C>T (p.Arg536Ter)	Pathogenic
2752020	NM_005050.4(ABCD4):c.1158dup (p.Phe387fs)	Pathogenic
2784087	NM_005050.4(ABCD4):c.7dup (p.Val3fs)	Pathogenic
280107	NM_005050.4(ABCD4):c.542+1G>T	Pathogenic
2843505	NM_005050.4(ABCD4):c.1438G>T (p.Glu480Ter)	Pathogenic
3013548	NM_005050.4(ABCD4):c.454C>T (p.Arg152Ter)	Pathogenic
3721580	NM_005050.4(ABCD4):c.442C>T (p.Gln148Ter)	Pathogenic
37320	NM_005050.4(ABCD4):c.1746_1747insCT (p.Glu583fs)	Pathogenic
37322	NM_005050.4(ABCD4):c.1456G>T (p.Gly486Cys)	Pathogenic
3902357	NM_005050.4(ABCD4):c.552_564del (p.Gly183_Trp184insTer)	Pathogenic
4525942	NM_005050.4(ABCD4):c.529C>T (p.Gln177Ter)	Pathogenic
4705101	NM_005050.4(ABCD4):c.1346del (p.Thr449fs)	Pathogenic
4733104	NM_005050.4(ABCD4):c.131del (p.Leu44fs)	Pathogenic
4744293	NM_005050.4(ABCD4):c.1246_1247del (p.Ser416fs)	Pathogenic
4767717	NM_005050.4(ABCD4):c.643del (p.Gln215fs)	Pathogenic
57808	GRCh38/hg38 14q24.3(chr14:73877072-78042422)x1	Pathogenic
1162192	GRCh37/hg19 14q22.2-24.3(chr14:54654001-75828024)x3	Likely pathogenic
155198	GRCh38/hg38 14q24.3-31.1(chr14:73343213-78835059)x1	Likely pathogenic
1698540	NM_005050.4(ABCD4):c.1295G>A (p.Arg432Gln)	Likely pathogenic
1722407	NC_000014.8:g.(74764773_74766250)(74769768?)del	Likely pathogenic
1878367	NM_005050.4(ABCD4):c.1118+1G>A	Likely pathogenic
2501162	NM_005050.4(ABCD4):c.1597_1598del (p.Ser533fs)	Likely pathogenic

SpliceAI

3301 predictions. Top by Δscore:

Variant	Effect	Δscore
14:74286812:AAGCA:A	acceptor_gain	1.0000
14:74286813:AGCA:A	acceptor_gain	1.0000
14:74286814:GCA:G	acceptor_gain	1.0000
14:74286815:CA:C	acceptor_gain	1.0000
14:74286815:CAC:C	acceptor_gain	1.0000
14:74286816:AC:A	acceptor_loss	1.0000
14:74286817:C:CC	acceptor_gain	1.0000
14:74286817:C:G	acceptor_loss	1.0000
14:74286818:T:G	acceptor_loss	1.0000
14:74286826:C:CT	acceptor_gain	1.0000
14:74286827:A:T	acceptor_gain	1.0000
14:74287806:TCA:T	donor_loss	1.0000
14:74287807:CACCT:C	donor_loss	1.0000
14:74287808:A:AG	donor_loss	1.0000
14:74287809:C:CA	donor_loss	1.0000
14:74287885:ACCTG:A	acceptor_loss	1.0000
14:74287888:T:A	acceptor_loss	1.0000
14:74288260:C:CC	acceptor_gain	1.0000
14:74290289:AC:A	donor_gain	1.0000
14:74290289:ACC:A	donor_gain	1.0000
14:74290290:CC:C	donor_gain	1.0000
14:74290290:CCC:C	donor_gain	1.0000
14:74292278:GCTAC:G	donor_loss	1.0000
14:74292279:CTACT:C	donor_loss	1.0000
14:74292280:TACTC:T	donor_loss	1.0000
14:74292281:ACT:A	donor_loss	1.0000
14:74292282:CTCA:C	donor_loss	1.0000
14:74292283:T:TC	donor_loss	1.0000
14:74292284:CACGT:C	donor_loss	1.0000
14:74292285:A:AC	donor_gain	1.0000

AlphaMissense

3950 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74295854:C:A	R223M	0.999
14:74286728:A:C	S575R	0.998
14:74286728:A:T	S575R	0.998
14:74286730:T:G	S575R	0.998
14:74292634:A:C	F315L	0.998
14:74292634:A:T	F315L	0.998
14:74292636:A:G	F315L	0.998
14:74292829:A:C	S285R	0.998
14:74292829:A:T	S285R	0.998
14:74292831:T:G	S285R	0.998
14:74295854:C:G	R223T	0.998
14:74295864:C:G	G220R	0.998
14:74295864:C:T	G220R	0.998
14:74286807:T:A	E549V	0.997
14:74287851:A:G	L532P	0.997
14:74287854:C:G	R531P	0.997
14:74288208:A:G	W520R	0.997
14:74288208:A:T	W520R	0.997
14:74292365:A:G	L347P	0.997
14:74292376:T:A	R343S	0.997
14:74292376:T:G	R343S	0.997
14:74292551:C:G	R343T	0.997
14:74295195:G:C	F224L	0.997
14:74295195:G:T	F224L	0.997
14:74295197:A:G	F224L	0.997
14:74296430:C:G	D149H	0.997
14:74296441:C:G	R145P	0.997
14:74297932:G:C	N141K	0.997
14:74297932:G:T	N141K	0.997
14:74298019:C:A	R112S	0.997

dbSNP variants (sampled 300 via entrez): RS1000015845 (14:74298267 C>T), RS1000085583 (14:74298470 C>T), RS1000389083 (14:74303928 G>A,C), RS1000621155 (14:74289037 G>A), RS1000686101 (14:74289857 T>C), RS1000936926 (14:74294427 T>C), RS1001521642 (14:74296768 G>A), RS1001524473 (14:74291511 A>C), RS1001583743 (14:74296504 G>A,C), RS1001865288 (14:74295552 G>A), RS1001984850 (14:74304734 C>A), RS1002018026 (14:74300799 A>C), RS1002099939 (14:74301013 C>G,T), RS1002201604 (14:74295701 A>C), RS1002205910 (14:74291748 G>C)

Disease associations

OMIM: gene MIM:603214 | disease phenotypes: MIM:614857, MIM:277400

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic acidemia with homocystinuria, type cblJ	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
methylmalonic acidemia with homocystinuria, type cblJ	Moderate	AR

Mondo (2): methylmalonic acidemia with homocystinuria, type cblJ (MONDO:0013925), methylmalonic aciduria and homocystinuria type cblC (MONDO:0010184)

Orphanet (3): Methylmalonic acidemia with homocystinuria, type cblJ (Orphanet:369955), Methylmalonic acidemia with homocystinuria (Orphanet:26), Methylmalonic acidemia with homocystinuria, type cblC (Orphanet:79282)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000888	Horizontal ribs
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001591	Bell-shaped thorax
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001680	Coarctation of aorta
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001895	Normochromic anemia
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002092	Pulmonary arterial hypertension
HP:0002156	Homocystinuria
HP:0002160	Hyperhomocystinemia
HP:0002533	Abnormal posturing
HP:0002750	Delayed skeletal maturation
HP:0002789	Tachypnea
HP:0002912	Methylmalonic acidemia
HP:0003145	Decreased circulating adenosylcobalamin concentration
HP:0003223	Decreased circulating methylcobalamin concentration
HP:0003524	Decreased methionine synthase activity

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	2
aristolochic acid I	increases expression	1
lead acetate	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Estradiol	decreases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vitamin B 12	affects metabolic processing	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B4GI	WG3630	Finite cell line	Male
CVCL_B4GJ	WG4066	Finite cell line	Female
CVCL_B4GK	WG4140	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns