Inborn disorder of cobalamin metabolism and transport

Summary

Inborn disorder of cobalamin metabolism and transport (MONDO:0019220) is a disease (an umbrella term covering 9 Mondo subtypes) caused by MMADHC (GenCC Definitive), with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include cyanocobalamin.

At a glance

• Causal gene: MMADHC (GenCC Definitive)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 2
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inborn disorder of cobalamin metabolism and transport
Mondo ID	MONDO:0019220
Orphanet	79171
DOID	DOID:0050731
ICD-11	936546617
UMLS	C5681844
MedGen	1826150
GARD	0018951
Is cancer (heuristic)	no

Also known as: cobalamin deficiency · hypocobalaminemia · inborn disorder of cobalamin metabolism and transport · inborn error of cobalamin metabolic process · inborn vitamin B12 deficiency (disease) · rare inborn error of cobalamin metabolic process

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn vitamin metabolic disorder › inborn disorder of cobalamin metabolism and transport

Related subtypes (4): familial isolated deficiency of vitamin E, neurodegenerative syndrome due to cerebral folate transport deficiency, disorders of vitamin D metabolism, cerebral folate deficiency

Subtypes (9): transcobalamin I deficiency, hereditary intrinsic factor deficiency, Imerslund-Grasbeck syndrome, transcobalamin II deficiency, methylmalonic acidemia due to transcobalamin receptor defect, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, homocystinuria without methylmalonic aciduria, methylmalonic aciduria and/or homocystinuria, cblD 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
MMADHC	Definitive	Autosomal recessive	inborn disorder of cobalamin metabolism and transport	6
THAP11	Limited	Autosomal recessive	inborn disorder of cobalamin metabolism and transport	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMADHC	Orphanet:308380	Methylcobalamin deficiency type cblDv1
MMADHC	Orphanet:308442	Vitamin B12-responsive methylmalonic acidemia, type cblDv2
MMADHC	Orphanet:79283	Methylmalonic acidemia with homocystinuria, type cblD

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
THAP11	HGNC:23194	ENSG00000168286	Q96EK4	THAP domain-containing protein 11	gencc
MMADHC	HGNC:25221	ENSG00000168288	Q9H3L0	Cobalamin trafficking protein CblD	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THAP11	THAP domain-containing protein 11	Transcription factor, which has both transcriptional activation and repression activities.
MMADHC	Cobalamin trafficking protein CblD	Involved in cobalamin metabolism and trafficking.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THAP11	Transcription factor	no		THAP_Znf
MMADHC	Other/Unknown	no		MMADHC

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amniotic fluid	1
primordial germ cell in gonad	1
skeletal muscle tissue of rectus abdominis	1
epithelium of nasopharynx	1
nasopharynx	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THAP11	289	ubiquitous	marker	amniotic fluid, skeletal muscle tissue of rectus abdominis, primordial germ cell in gonad
MMADHC	294	ubiquitous	marker	palpebral conjunctiva, epithelium of nasopharynx, nasopharynx

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMADHC	1,201
THAP11	789

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMADHC	Q9H3L0	4
THAP11	Q96EK4	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 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 MMADHC causes MMAHCD	1	3806.7×	0.003	MMADHC
Cobalamin (Cbl) metabolism	1	1268.9×	0.003	MMADHC
Defects in cobalamin (B12) metabolism	1	815.7×	0.003	MMADHC
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.003	MMADHC
Defects in vitamin and cofactor metabolism	1	601.0×	0.003	MMADHC
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	MMADHC
Metabolism of vitamins and cofactors	1	116.5×	0.012	MMADHC
Diseases of metabolism	1	80.4×	0.016	MMADHC
Disease	1	13.1×	0.085	MMADHC
Metabolism	1	11.6×	0.086	MMADHC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of mitochondrial transcription	1	936.2×	0.003	THAP11
cobalamin metabolic process	1	766.0×	0.003	MMADHC
electron transport chain	1	766.0×	0.003	THAP11
negative regulation of neuron apoptotic process	1	55.4×	0.026	THAP11
cell population proliferation	1	51.4×	0.026	THAP11
neuron differentiation	1	50.1×	0.026	THAP11
negative regulation of transcription by RNA polymerase II	1	8.9×	0.125	THAP11
regulation of transcription by RNA polymerase II	1	5.8×	0.164	THAP11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THAP11	0	0
MMADHC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MMADHC	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	THAP11, MMADHC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THAP11	0	—
MMADHC	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYANOCOBALAMIN	4	1