homocystinuria-megaloblastic anemia cblD type

Summary

homocystinuria-megaloblastic anemia cblD type (MONDO:0700297) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	homocystinuria-megaloblastic anemia cblD type
Mondo ID	MONDO:0700297
OMIM	620952
UMLS	C1848553
MedGen	341254
GARD	0027384
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › 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 › homocystinuria › homocystinuria without methylmalonic aciduria › homocystinuria-megaloblastic anemia cblD type

Related subtypes (3): methylcobalamin deficiency type cblE, methylcobalamin deficiency type cblG, methylcobalamin deficiency type cblDv1

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
761	NM_015702.3(MMADHC):c.776T>C (p.Leu259Pro)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
762	NM_015702.3(MMADHC):c.545C>A (p.Thr182Asn)	MMADHC	Pathogenic	no assertion criteria provided
763	NM_015702.3(MMADHC):c.746A>G (p.Tyr249Cys)	MMADHC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMADHC	HGNC:25221	ENSG00000168288	Q9H3L0	Cobalamin trafficking protein CblD	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMADHC	Cobalamin trafficking protein CblD	Involved in cobalamin metabolism and trafficking.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMADHC	Other/Unknown	no		MMADHC

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
epithelium of nasopharynx	1
nasopharynx	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMADHC	Q9H3L0	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cobalamin metabolic process	1	1532.0×	7e-04	MMADHC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
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: 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MMADHC

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)
MMADHC	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.