MMADHC

Summary

MMADHC (metabolism of cobalamin associated D, HGNC:25221) is a protein-coding gene on chromosome 2q23.2, encoding Cobalamin trafficking protein CblD (Q9H3L0). Involved in cobalamin metabolism and trafficking.

This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.

Source: NCBI Gene 27249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inborn disorder of cobalamin metabolism and transport (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 394 total — 36 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015702

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25221
Approved symbol	MMADHC
Name	metabolism of cobalamin associated D
Location	2q23.2
Locus type	gene with protein product
Status	Approved
Aliases	CL25022, cblD
Ensembl gene	ENSG00000168288
Ensembl biotype	protein_coding
OMIM	611935
Entrez	27249

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000303319, ENST00000422782, ENST00000428879, ENST00000460311, ENST00000893992, ENST00000893993, ENST00000893994, ENST00000893995, ENST00000893996, ENST00000893997, ENST00000934248, ENST00000934249, ENST00000934250, ENST00000949352

RefSeq mRNA: 1 — MANE Select: NM_015702 NM_015702

CCDS: CCDS2189

Canonical transcript exons

ENST00000303319 — 8 exons

Exon	Start	End
ENSE00001124846	149576437	149576542
ENSE00001124850	149579431	149579648
ENSE00001124856	149587089	149587149
ENSE00001151401	149582127	149582271
ENSE00001698248	149587664	149587775
ENSE00001730775	149569637	149570168
ENSE00003343887	149575711	149575841
ENSE00003409579	149571085	149571171

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 77.7126 / max 1595.5053, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31083	73.8953	1824
31084	1.9759	1294
31082	1.6321	991
31080	0.1508	49
31081	0.0586	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	99.41	gold quality
epithelium of nasopharynx	UBERON:0001951	99.37	gold quality
nasopharynx	UBERON:0001728	99.36	gold quality
amniotic fluid	UBERON:0000173	99.35	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.25	gold quality
esophagus squamous epithelium	UBERON:0006920	99.24	gold quality
epithelium of esophagus	UBERON:0001976	99.23	gold quality
biceps brachii	UBERON:0001507	99.21	gold quality
tongue squamous epithelium	UBERON:0006919	99.19	gold quality
vastus lateralis	UBERON:0001379	99.18	gold quality
parotid gland	UBERON:0001831	99.16	gold quality
quadriceps femoris	UBERON:0001377	99.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.11	gold quality
oral cavity	UBERON:0000167	99.10	gold quality
parietal pleura	UBERON:0002400	99.10	gold quality
eye	UBERON:0000970	99.04	gold quality
deltoid	UBERON:0001476	99.04	gold quality
body of tongue	UBERON:0011876	99.02	gold quality
cartilage tissue	UBERON:0002418	99.01	gold quality
diaphragm	UBERON:0001103	98.98	gold quality
tongue	UBERON:0001723	98.97	gold quality
pleura	UBERON:0000977	98.94	gold quality
myocardium	UBERON:0002349	98.93	gold quality
pharyngeal mucosa	UBERON:0000355	98.92	gold quality
tibia	UBERON:0000979	98.92	gold quality
trabecular bone tissue	UBERON:0002483	98.92	gold quality
superior surface of tongue	UBERON:0007371	98.92	gold quality
adult organism	UBERON:0007023	98.90	gold quality
gingiva	UBERON:0001828	98.89	gold quality
gingival epithelium	UBERON:0001949	98.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting MMADHC, 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-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548J-3P	99.94	72.61	4881
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-4760-3P	99.93	70.50	2385
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-10395-3P	98.10	66.70	1726
HSA-MIR-192-3P	97.52	67.66	1001

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• mutations in a gene designated MMADHC (currently named C2orf25) are responsible for the cblD defect in vitamin B12 metabolism; various mutations are associated with each of the three biochemical phenotypes of the disorder (PMID:18385497)
• MMADHC was confirmed as a binding partner for MMACHC both in vitro (SPR) and in vivo (bacterial two-hybrid system). (PMID:21071249)
• MMADHC mutations are associated with methylmalonic aciduria and homocystinuria. (PMID:22156578)
• The function of MMADHC is exerted through its structured C-terminal domain via interactions with MMACHC. (PMID:22832074)
• Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism. (PMID:23270877)
• specific regions of MMADHC are involved in differential regulation of adenosylcobalamin and methylcobalamin synthesis (PMID:24722857)
• analysis of crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway (PMID:26364851)
• the MMACHC-MMADHC complex is a 1:1 heterodimer, where the interaction region overlaps with the MMACHC-Cbl binding site (PMID:26483544)
• These data show that the processing of cobalamin in cytoplasm occurs in a multiprotein complex composed of at least methionine synthase, methionine synthase reductase, MMACHC and MMADHC. (PMID:27771510)
• The study of genes involved in methylmalonic acidaemia with homocystinuria detected a homozygous mutation (c.748C>T) in the MMADHC gene (found in the DNA of both sisters), which generates a stop codon that results in a truncated protein, provoking the disease. (PMID:28939051)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmadhcb	ENSDARG00000005870
danio_rerio	mmadhca	ENSDARG00000041602
mus_musculus	Mmadhc	ENSMUSG00000026766
rattus_norvegicus	Mmadhc	ENSRNOG00000004740
caenorhabditis_elegans		WBGENE00013577

Protein

Protein identifiers

Cobalamin trafficking protein CblD — Q9H3L0 (reviewed: Q9H3L0)

Alternative names: CblD, Methylmalonic aciduria and homocystinuria type D protein, mitochondrial

All UniProt accessions (2): Q9H3L0, F8WEC0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cobalamin metabolism and trafficking. Plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5’-deoxyadenosylcobalamin (AdoCbl). Promotes oxidation of cob(II)alamin bound to MMACHC. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine.

Subunit / interactions. Heterodimer with MMACHC. Forms a multiprotein complex with MMACHC, MTR and MTRR.

Subcellular location. Cytoplasm. Mitochondrion.

Tissue specificity. Widely expressed at high levels.

Disease relevance. Methylmalonic aciduria and homocystinuria, cblD type (MAHCD) [MIM:277410] An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, intellectual disability, seizures, and megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria. The disease is caused by variants affecting the gene represented in this entry. Homocystinuria-megaloblastic anemia, cblD type (HMAD) [MIM:620952] An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. HMAD appears in infancy or early childhood and is characterized by delayed psychomotor development, dystonia or spastic ataxia, poor speech, megaloblastic anemia, homocystinuria, and hypomethioninemia. Additional features may include nystagmus, poor eye contact, hypotonia, and seizures. Brain imaging shows cerebral or cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry. Methylmalonic aciduria, cblD type (MACD) [MIM:620953] A form of methylmalonic aciduria, an inborn error of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin. MACD is an autosomal recessive form characterized by severe clinical features including respiratory distress syndrome, intracranial hemorrhage, seizures, and ketotic coma. Laboratory studies show isolated methylmalonic aciduria without homocystinuria. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_056517* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019362	MMADHC	Family

Pfam: PF10229

UniProt features (38 total): mutagenesis site 12, strand 7, sequence variant 7, helix 5, sequence conflict 2, turn 2, transit peptide 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5CV0	X-RAY DIFFRACTION	1.9
5CUZ	X-RAY DIFFRACTION	2.31
6X8Z	X-RAY DIFFRACTION	2.5
9MRS	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3L0-F1	77.67	0.48

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 203

Mutagenesis-validated functional residues (12):

Position	Phenotype
165	mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.
186	decreases methylcobalamin levels. no effect on interaction with mmachc.
189	decreases methylcobalamin levels. impairs interaction with mmachc.
197	decreases methylcobalamin levels, but increases adenosylcobalamin levels.
204	decreases methylcobalamin levels and mildly increases adenosylcobalamin levels.
212	no effect on cobalamin levels.
226	decreases methylcobalamin levels, but increases adenosylcobalamin levels. no effect on interaction with mmachc.
237	mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.
266	mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.
270	decreases methylcobalamin levels.
278	marginally decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.
280	no effect on cobalamin levels.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-3359473	Defective MMADHC causes MMAHCD
R-HSA-9759218	Cobalamin (Cbl) metabolism
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-5668914	Diseases of metabolism

MSigDB gene sets: 229 (showing top): GOBP_COBALAMIN_METABOLIC_PROCESS, GNF2_XRCC5, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, REACTOME_METABOLISM_OF_VITAMINS_AND_COFACTORS, ALFANO_MYC_TARGETS, GOMF_MOLECULAR_CARRIER_ACTIVITY, REACTOME_COBALAMIN_CBL_VITAMIN_B12_TRANSPORT_AND_METABOLISM, REACTOME_METABOLISM_OF_WATER_SOLUBLE_VITAMINS_AND_COFACTORS, REACTOME_DEFECTS_IN_COBALAMIN_B12_METABOLISM, REACTOME_DEFECTS_IN_VITAMIN_AND_COFACTOR_METABOLISM, REACTOME_DISEASES_OF_METABOLISM, E2F2_TARGET_GENES, FEV_TARGET_GENES, HHEX_TARGET_GENES

GO Biological Process (1): cobalamin metabolic process (GO:0009235)

GO Molecular Function (2): molecular carrier activity (GO:0140104), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Defects in cobalamin (B12) metabolism	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	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
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
cytoplasm	2
tetrapyrrole metabolic process	1
molecular_function	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMADHC	LMBRD1	Q9NUN5	989
MMADHC	MMAA	Q8IVH4	983
MMADHC	MMAB	Q96EY8	977
MMADHC	MMACHC	Q9Y4U1	964
MMADHC	MTRR	Q9UBK8	957
MMADHC	MMUT	P22033	955
MMADHC	MTR	Q99707	955
MMADHC	CD320	Q9NPF0	863
MMADHC	MCEE	Q96PE7	801
MMADHC	CBL	P22681	792
MMADHC	MTHFR	P42898	734
MMADHC	ABCD4	O14678	714
MMADHC	H7C2H4	H7C2H4	702
MMADHC	P0DN79	P0DN79	682
MMADHC	ACSF3	Q4G176	595

IntAct

56 interactions, top by confidence:

A	B	Type	Score
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
	MMADHC	psi-mi:“MI:0407”(direct interaction)	0.560
CREB5	MMADHC	psi-mi:“MI:0915”(physical association)	0.560
POU4F2	MMADHC	psi-mi:“MI:0915”(physical association)	0.560
MMADHC	TBC1D7	psi-mi:“MI:0915”(physical association)	0.560
CINP	MMADHC	psi-mi:“MI:0915”(physical association)	0.560
C1orf94	USO1	psi-mi:“MI:0914”(association)	0.550
SPMIP6	DCTN6	psi-mi:“MI:0914”(association)	0.530
MRPS24	ZZEF1	psi-mi:“MI:0914”(association)	0.530
RASL10B	AHCYL1	psi-mi:“MI:0914”(association)	0.530
FBXO11	LONP1	psi-mi:“MI:0914”(association)	0.530
SPMIP6	LONP1	psi-mi:“MI:0914”(association)	0.530
MKLN1	HTRA2	psi-mi:“MI:0914”(association)	0.510
AURKAIP1	NRDC	psi-mi:“MI:0914”(association)	0.480
KIF12	MMADHC	psi-mi:“MI:0915”(physical association)	0.400
Tmed2		psi-mi:“MI:0914”(association)	0.350
NDUFS7		psi-mi:“MI:0914”(association)	0.350
FGL1	DNM1L	psi-mi:“MI:0914”(association)	0.350
SFPQ	PRMT5	psi-mi:“MI:0914”(association)	0.350
AURKAIP1	HNRNPR	psi-mi:“MI:0914”(association)	0.350
C1orf94	USO1	psi-mi:“MI:0914”(association)	0.350
	PMPCB	psi-mi:“MI:0914”(association)	0.350
SDHB	CLPX	psi-mi:“MI:0914”(association)	0.350
CISD3	POLRMT	psi-mi:“MI:0914”(association)	0.350
MAP7	CASC3	psi-mi:“MI:0914”(association)	0.350
GIGYF1	EIF3H	psi-mi:“MI:0914”(association)	0.350

BioGRID (47): MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS), MMADHC (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3MU35, A0A0D3MU50, A2T1U1, B9DHG0, B9F4I8, E5KCJ8, F4HZK4, F4I933, F4J117, F4JLC1, M1C5M7, P10349, Q2QTC2, Q39639, Q3UD82, Q42463, Q4QQM5, Q53NI2, Q5N800, Q67Y99, Q7SZC5, Q7Y220, Q8H0W0, Q8NAN2, Q8RWG3, Q8VYD8, Q8VYL1, Q8W4K5, Q93YW0, Q940U6, Q944I4, Q94AX2, Q94CJ5, Q9C4Z7, Q9C5W3, Q9C642, Q9FEQ0, Q9FIG9, Q9FKF4, Q9FMX6

Diamond homologs: Q5ZKP2, Q6AYQ6, Q99LS1, Q9H3L0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	29
Uncertain significance	92
Likely benign	180
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072551	NC_000002.11:g.(?150443583)(150443631_?)del	Pathogenic
1432468	NM_015702.3(MMADHC):c.692T>A (p.Leu231Ter)	Pathogenic
1436154	NM_015702.3(MMADHC):c.433A>T (p.Arg145Ter)	Pathogenic
1455539	NM_015702.3(MMADHC):c.585_588del (p.Arg197fs)	Pathogenic
1456251	NM_015702.3(MMADHC):c.352C>T (p.Gln118Ter)	Pathogenic
1458974	NC_000002.11:g.(?150438631)(150438795_?)del	Pathogenic
1459027	NM_015702.3(MMADHC):c.638_642del (p.Tyr213fs)	Pathogenic
1963718	NM_015702.3(MMADHC):c.202C>T (p.Gln68Ter)	Pathogenic
2012128	NM_015702.3(MMADHC):c.151dup (p.Ile51fs)	Pathogenic
2030444	NM_015702.3(MMADHC):c.240_241insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGGAACATAGGTTTT (p.Asp81delinsPhePhePhePhePhePheXaaXaaXaaXaaLeuThrSerTer)	Pathogenic
2096130	NM_015702.3(MMADHC):c.546_547del (p.Lys183fs)	Pathogenic
219000	NM_015702.3(MMADHC):c.228dup (p.Asn77fs)	Pathogenic
219001	NM_015702.3(MMADHC):c.60_61insAT (p.Leu21fs)	Pathogenic
219002	NM_015702.3(MMADHC):c.455dup (p.Cys153fs)	Pathogenic
2426213	NC_000002.11:g.(?150443583)(150443611_?)del	Pathogenic
265247	NM_015702.3(MMADHC):c.472C>T (p.Arg158Ter)	Pathogenic
2694795	NM_015702.3(MMADHC):c.233_248dup (p.His83_Leu84insArgPheTer)	Pathogenic
2701308	NM_015702.3(MMADHC):c.22dup (p.Arg8fs)	Pathogenic
2734282	NM_015702.3(MMADHC):c.538C>T (p.Gln180Ter)	Pathogenic
2779693	NM_015702.3(MMADHC):c.171G>A (p.Trp57Ter)	Pathogenic
2832478	NM_015702.3(MMADHC):c.634dup (p.Cys212fs)	Pathogenic
2850205	NM_015702.3(MMADHC):c.391dup (p.Glu131fs)	Pathogenic
2989373	NM_015702.3(MMADHC):c.566G>A (p.Trp189Ter)	Pathogenic
3247250	NC_000002.11:g.(?150426488)(150443611_?)del	Pathogenic
3247251	NC_000002.11:g.(?150426488)(150426702_?)del	Pathogenic
487521	NM_015702.3(MMADHC):c.24_25del (p.Arg8fs)	Pathogenic
639047	NM_015702.3(MMADHC):c.295_296del (p.Leu99fs)	Pathogenic
762	NM_015702.3(MMADHC):c.545C>A (p.Thr182Asn)	Pathogenic
764	NM_015702.3(MMADHC):c.57_64del (p.Cys19_Ser20insTer)	Pathogenic
765	NM_015702.3(MMADHC):c.160C>T (p.Arg54Ter)	Pathogenic

SpliceAI

964 predictions. Top by Δscore:

Variant	Effect	Δscore
2:149570164:AAAAA:A	acceptor_gain	1.0000
2:149570165:AAAA:A	acceptor_gain	1.0000
2:149570166:AAA:A	acceptor_gain	1.0000
2:149570166:AAAC:A	acceptor_loss	1.0000
2:149570167:AA:A	acceptor_gain	1.0000
2:149570168:ACTG:A	acceptor_loss	1.0000
2:149570169:C:CC	acceptor_gain	1.0000
2:149570169:C:CG	acceptor_loss	1.0000
2:149570170:T:C	acceptor_loss	1.0000
2:149570177:A:C	acceptor_gain	1.0000
2:149571077:TTAC:T	donor_loss	1.0000
2:149571078:TAC:T	donor_loss	1.0000
2:149571079:A:AC	donor_gain	1.0000
2:149571079:ACT:A	donor_loss	1.0000
2:149571080:C:CC	donor_gain	1.0000
2:149571080:CTCA:C	donor_gain	1.0000
2:149571081:TC:T	donor_loss	1.0000
2:149571082:CAC:C	donor_loss	1.0000
2:149571083:A:AC	donor_gain	1.0000
2:149571083:A:T	donor_loss	1.0000
2:149571083:ACTG:A	donor_gain	1.0000
2:149571084:C:CA	donor_gain	1.0000
2:149571084:CT:C	donor_gain	1.0000
2:149571084:CTG:C	donor_gain	1.0000
2:149571084:CTGC:C	donor_gain	1.0000
2:149571168:TGAA:T	acceptor_gain	1.0000
2:149571172:C:CC	acceptor_gain	1.0000
2:149575706:ATTAC:A	donor_loss	1.0000
2:149575707:TTA:T	donor_loss	1.0000
2:149575708:TAC:T	donor_loss	1.0000

AlphaMissense

1945 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:149571158:G:T	A208D	0.999
2:149570104:A:G	F254S	0.998
2:149571092:C:T	G230D	0.998
2:149571159:C:G	A208P	0.998
2:149570035:C:T	G277E	0.997
2:149570080:C:T	C262Y	0.997
2:149570081:A:G	C262R	0.997
2:149570031:A:C	S278R	0.996
2:149570031:A:T	S278R	0.996
2:149570033:T:G	S278R	0.996
2:149570036:C:G	G277R	0.996
2:149570036:C:T	G277R	0.996
2:149570079:A:C	C262W	0.996
2:149571109:A:C	F224L	0.996
2:149571109:A:T	F224L	0.996
2:149571111:A:G	F224L	0.996
2:149571116:G:T	A222D	0.996
2:149571117:C:G	A222P	0.996
2:149571137:A:G	L215P	0.996
2:149575793:A:G	L176P	0.996
2:149579634:A:G	W57R	0.996
2:149579634:A:T	W57R	0.996
2:149570057:A:G	W270R	0.995
2:149570057:A:T	W270R	0.995
2:149570089:A:G	L259P	0.995
2:149571092:C:A	G230V	0.995
2:149571110:A:G	F224S	0.995
2:149571114:C:G	D223H	0.995
2:149575755:A:G	W189R	0.995
2:149575755:A:T	W189R	0.995

dbSNP variants (sampled 300 via entrez): RS1000122684 (2:149583409 A>T), RS1000175487 (2:149583777 C>T), RS1000538742 (2:149570794 A>G), RS1000653453 (2:149570422 T>C), RS1000732087 (2:149577140 G>A), RS1001270584 (2:149581855 G>A), RS1001300169 (2:149588169 A>G), RS1001460430 (2:149582544 T>C), RS1001541662 (2:149588427 T>G), RS1001555373 (2:149569781 G>A,T), RS1001733291 (2:149583319 C>T), RS1001975207 (2:149589128 T>C,G), RS1002245175 (2:149576780 C>T), RS1002289378 (2:149571278 A>T), RS1002335478 (2:149587868 G>A)

Disease associations

OMIM: gene MIM:611935 | disease phenotypes: MIM:277410, MIM:277400, MIM:620952, MIM:620953

GenCC curated gene-disease

Disease	Classification	Inheritance
inborn disorder of cobalamin metabolism and transport	Definitive	Autosomal recessive
methylmalonic aciduria and homocystinuria type cblD	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
inborn disorder of cobalamin metabolism and transport	Definitive	AR

Mondo (5): methylmalonic aciduria and homocystinuria type cblD (MONDO:0010185), methylmalonic aciduria and homocystinuria type cblC (MONDO:0010184), homocystinuria-megaloblastic anemia cblD type (MONDO:0700297), isolated methylmalonic aciduria cblD type (MONDO:0700298), inborn disorder of cobalamin metabolism and transport (MONDO:0019220)

Orphanet (4): Homocystinuria without methylmalonic aciduria (Orphanet:622), Methylmalonic acidemia with homocystinuria, type cblD (Orphanet:79283), Methylmalonic acidemia with homocystinuria (Orphanet:26), Methylmalonic acidemia with homocystinuria, type cblC (Orphanet:79282)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000666	Horizontal nystagmus
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000718	Aggressive behavior
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0000980	Pallor
HP:0001083	Ectopia lentis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001310	Dysmetria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001348	Brisk reflexes
HP:0001508	Failure to thrive
HP:0001622	Premature birth
HP:0001873	Thrombocytopenia
HP:0001882	Decreased total leukocyte count

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002207_5	Liver enzyme levels (alanine transaminase)	2.000000e-07
GCST003518_13	Daytime sleep phenotypes	4.000000e-06
GCST010168_2	Neonatal total 25-hydroxyvitamin D levels (fetal genetic effect)	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564743	Methylmalonic Aciduria and Homocystinuria, CblD Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879517 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Dronabinol	decreases expression, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases reaction, affects binding	1
zinc chromate	increases abundance, increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
chloropicrin	affects expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Potassium Dichromate	decreases expression	1
Thiram	increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin M1	decreases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4823873	Binding	Binding affinity to MMADHC in human Flp-In-T-REx-293 stably expressing 3X-FLAG-tagged LOPN1 assessed as increase in protein abundance by mass spectrometric analysis	Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3B3	Abcam HEK293T MMADHC KO	Transformed cell line	Female
CVCL_B4EM	WG1220	Finite cell line	Male
CVCL_B4EN	WG1437	Finite cell line	Male
CVCL_B4EP	WG3280	Finite cell line	Male
CVCL_B4EQ	WG3583	Finite cell line	Female
CVCL_B4ER	WG3745	Finite cell line	Female
CVCL_B4F7	WG3646	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02679833	Not specified	COMPLETED	Effect of Toothpaste Fortified With Cyanocobalamin on Vitamin B12 Status
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns