methylmalonic acidemia with homocystinuria, type cblJ

Summary

methylmalonic acidemia with homocystinuria, type cblJ (MONDO:0013925) is a disease caused by ABCD4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABCD4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 363

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic acidemia with homocystinuria, type cblJ
Mondo ID	MONDO:0013925
OMIM	614857
Orphanet	369955
UMLS	C3553915
MedGen	766829
GARD	0012621
Is cancer (heuristic)	no

Also known as: cblJ defects · cobalamin J defect · combined defect in adenosylcobalamin and methylcobalamin synthesis, type cblJ · MAHCJ · methylmalonic acidemia with homocystinuria type cblJ · methylmalonic aciduria and homocystinuria, cblJ type · methylmalonic aciduria with homocystinuria, type cblJ

Data availability: 363 ClinVar variants · 5 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › methylmalonic acidemia › methylmalonic aciduria and homocystinuria › methylmalonic acidemia with homocystinuria, type cblJ

Related subtypes (5): methylmalonic aciduria and homocystinuria type cblF, methylmalonic aciduria and homocystinuria type cblC, methylmalonic aciduria and homocystinuria type cblD, methylmalonic acidemia with homocystinuria, type cblX, methylmalonic aciduria and homocystinuria, cb1L type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

363 retrieved; paginated sample, class counts are floors:

164 likely benign, 114 uncertain significance, 24 benign, 18 pathogenic, 18 likely pathogenic, 13 conflicting classifications of pathogenicity, 9 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069117	NM_005050.4(ABCD4):c.1294del (p.Arg432fs)	ABCD4	Pathogenic	criteria provided, single submitter
1335925	NM_005050.4(ABCD4):c.1125del (p.Trp377fs)	ABCD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1343599	NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)	ABCD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453520	NC_000014.8:g.(?74766231)(74769615_?)del	ABCD4	Pathogenic	criteria provided, single submitter
1941455	NM_005050.4(ABCD4):c.1213_1214dup (p.Asp406fs)	ABCD4	Pathogenic	criteria provided, single submitter
2141575	NM_005050.4(ABCD4):c.373del (p.Arg125fs)	ABCD4	Pathogenic	criteria provided, single submitter
2728334	NM_005050.4(ABCD4):c.1606C>T (p.Arg536Ter)	ABCD4	Pathogenic	criteria provided, single submitter
2752020	NM_005050.4(ABCD4):c.1158dup (p.Phe387fs)	ABCD4	Pathogenic	criteria provided, single submitter
2784087	NM_005050.4(ABCD4):c.7dup (p.Val3fs)	ABCD4	Pathogenic	criteria provided, single submitter
280107	NM_005050.4(ABCD4):c.542+1G>T	ABCD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2843505	NM_005050.4(ABCD4):c.1438G>T (p.Glu480Ter)	ABCD4	Pathogenic	criteria provided, single submitter
3013548	NM_005050.4(ABCD4):c.454C>T (p.Arg152Ter)	ABCD4	Pathogenic	criteria provided, single submitter
3576745	NM_005050.4(ABCD4):c.528C>A (p.Tyr176Ter)	ABCD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3721580	NM_005050.4(ABCD4):c.442C>T (p.Gln148Ter)	ABCD4	Pathogenic	criteria provided, single submitter
37320	NM_005050.4(ABCD4):c.1746_1747insCT (p.Glu583fs)	ABCD4	Pathogenic	no assertion criteria provided
37322	NM_005050.4(ABCD4):c.1456G>T (p.Gly486Cys)	ABCD4	Pathogenic	no assertion criteria provided
4705101	NM_005050.4(ABCD4):c.1346del (p.Thr449fs)	ABCD4	Pathogenic	criteria provided, single submitter
4733104	NM_005050.4(ABCD4):c.131del (p.Leu44fs)	ABCD4	Pathogenic	criteria provided, single submitter
4744293	NM_005050.4(ABCD4):c.1246_1247del (p.Ser416fs)	ABCD4	Pathogenic	criteria provided, multiple submitters, no conflicts
4767717	NM_005050.4(ABCD4):c.643del (p.Gln215fs)	ABCD4	Pathogenic	criteria provided, single submitter
583152	NM_005050.4(ABCD4):c.1588C>T (p.Gln530Ter)	ABCD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698540	NM_005050.4(ABCD4):c.1295G>A (p.Arg432Gln)	ABCD4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664286	NM_005050.4(ABCD4):c.301del (p.Gln101fs)	ABCD4	Likely pathogenic	criteria provided, single submitter
2720728	NM_005050.4(ABCD4):c.1457-1G>C	ABCD4	Likely pathogenic	criteria provided, single submitter
3576735	NM_005050.4(ABCD4):c.1343_1349delinsCCCATGGG (p.Leu448fs)	ABCD4	Likely pathogenic	criteria provided, single submitter
3576737	NM_005050.4(ABCD4):c.1237G>T (p.Glu413Ter)	ABCD4	Likely pathogenic	criteria provided, single submitter
3576738	NM_005050.4(ABCD4):c.1118+1G>T	ABCD4	Likely pathogenic	criteria provided, single submitter
3576739	NM_005050.4(ABCD4):c.936+1G>A	ABCD4	Likely pathogenic	criteria provided, single submitter
3576740	NM_005050.4(ABCD4):c.767dup (p.Leu257fs)	ABCD4	Likely pathogenic	criteria provided, single submitter
3576741	NM_005050.4(ABCD4):c.708del (p.Ala237fs)	ABCD4	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABCD4	Strong	Autosomal recessive	methylmalonic acidemia with homocystinuria, type cblJ	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCD4	Orphanet:369955	Methylmalonic acidemia with homocystinuria, type cblJ

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCD4	HGNC:68	ENSG00000119688	O14678	Lysosomal cobalamin transporter ABCD4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCD4	Lysosomal cobalamin transporter ABCD4	Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCD4	Transporter	yes	7.6.2.8	ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	1
right ovary	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCD4	259	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCD4	1,327

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD4	O14678	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD4 causes MAHCJ	1	5710.0×	0.002	ABCD4
Transport of RCbl within the body	1	1427.5×	0.004	ABCD4
Uptake of dietary cobalamins into enterocytes	1	1142.0×	0.004	ABCD4
Defects in cobalamin (B12) metabolism	1	815.7×	0.004	ABCD4
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.004	ABCD4
Defects in vitamin and cofactor metabolism	1	601.0×	0.004	ABCD4
ABC transporter disorders	1	439.2×	0.004	ABCD4
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	ABCD4
Disorders of transmembrane transporters	1	139.3×	0.010	ABCD4
Metabolism of vitamins and cofactors	1	116.5×	0.011	ABCD4
Diseases of metabolism	1	80.4×	0.015	ABCD4
Disease	1	13.1×	0.083	ABCD4
Metabolism	1	11.6×	0.086	ABCD4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
long-chain fatty acid import into peroxisome	1	3370.4×	0.001	ABCD4
very long-chain fatty acid catabolic process	1	2407.4×	0.001	ABCD4
cobalamin transport	1	1872.4×	0.001	ABCD4
cobalamin metabolic process	1	1532.0×	0.001	ABCD4
peroxisome organization	1	802.5×	0.002	ABCD4
fatty acid beta-oxidation	1	374.5×	0.004	ABCD4
transmembrane transport	1	168.5×	0.006	ABCD4
cellular response to leukemia inhibitory factor	1	159.0×	0.006	ABCD4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCD4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD4	7.6.2.8	ABC-type vitamin B12 transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCD4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.