Megaloblastic anemia

Summary

Megaloblastic anemia (MONDO:0001700) is a disease (an umbrella term covering 6 Mondo subtypes) with 2 cohort genes (10 GWAS associations across 6 studies).

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 2
• GWAS associations: 10
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megaloblastic anemia
Mondo ID	MONDO:0001700
DOID	DOID:13382
NCIT	C34382
SNOMED CT	53165003
UMLS	C0002888
MedGen	1527
Is cancer (heuristic)	no

Also known as: megaloblastic anaemia (disease) · megaloblastic anemia · megaloblastic anemia (disease)

Data availability: 2 ClinVar variants · 10 GWAS associations (6 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › macrocytic anemia › megaloblastic anemia

Related subtypes (1): myelodysplastic syndrome associated with isolated del(5q)

Subtypes (6): pernicious anemia, hereditary folate malabsorption, formiminoglutamic aciduria, Imerslund-Grasbeck syndrome, constitutional megaloblastic anemia with severe neurologic disease, vitamin B12- and folate-independent constitutional megaloblastic anemia

Genetics & variants

GWAS landscape

10 GWAS associations across 6 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs34324219	3e-63	TCN1	C	0.3
rs503644	4e-56	TCN1 - OOSP3	T	0.9
rs1801222	4e-46	CUBN	A	0.18
rs601338	1e-33	FUT2	G	0.15
rs1131603	3e-24	TCN2	T	0.34
chr6:49445306	4e-20		T	0.11
chr19:5839746	3e-13		G	0.18
chr19:8373778	1e-11		G	0.19
rs116075662	1e-11	MMAA	G	0.18
rs187896863	7e-10	PRDX4P1 - THAP12P9	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475774	Verma A	2024	13,771	426,909	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475773	Verma A	2024	3,353	115,939	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480950	Verma A	2024	3,353	115,939	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477448	Verma A	2024	1,566	57,186	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435797	Zhou W	2018	1,076	390,026	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651294	Liu TY	2025	359	215,243	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	7
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
missense_variant	3
unknown	3
intergenic_variant	2
stop_gained	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs34324219	11	59855905	C>A	0.113	missense_variant	TCN1	3e-63	Tier 1: coding
rs503644	11	59873981	T>A,C	0.032	intergenic_variant	TCN1 - OOSP3	4e-56	Tier 4: intronic/intergenic
rs1801222	10	17114152	A>C,G,T	0.343	missense_variant	CUBN	4e-46	Tier 1: coding
rs601338	19	48703417	G>A	0.488	stop_gained	FUT2	1e-33	Tier 1: coding
rs1131603	22	30622988	T>C	0.05	missense_variant	TCN2	3e-24	Tier 1: coding
chr6:49445306				0.364			4e-20	Tier 4: intronic/intergenic
chr19:5839746				0.481			3e-13	Tier 4: intronic/intergenic
chr19:8373778				0.302			1e-11	Tier 4: intronic/intergenic
rs116075662	4	145653003	G>A	0.049	intron_variant	MMAA	1e-11	Tier 4: intronic/intergenic
rs187896863	4	45143384	C>A		intergenic_variant	PRDX4P1 - THAP12P9	7e-10	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523538	NM_030943.4(AMN):c.320_321dup (p.Asp108fs)	AMN	Pathogenic	criteria provided, single submitter
523537	NM_030943.4(AMN):c.149T>C (p.Phe50Ser)	AMN	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMN	Orphanet:35858	Imerslund-Gräsbeck syndrome
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

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
AMN	HGNC:14604	ENSG00000166126	Q9BXJ7	Protein amnionless	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMN	Protein amnionless	Membrane-bound component of the endocytic receptor formed by AMN and CUBN.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMN	Other/Unknown	no		AMN
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

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
duodenum	1
jejunal mucosa	1
mucosa of transverse colon	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMN	223	broad	marker	mucosa of transverse colon, jejunal mucosa, duodenum
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCD1	1,181
AMN	414

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
AMN	Q9BXJ7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	2855.0×	0.005	ABCD1
Defective AMN causes MGA1	1	1903.3×	0.005	AMN
Defective CUBN causes MGA1	1	1903.3×	0.005	AMN
HDL clearance	1	1142.0×	0.006	AMN
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	951.7×	0.006	ABCD1
Linoleic acid (LA) metabolism	1	571.0×	0.006	ABCD1
Uptake of dietary cobalamins into enterocytes	1	571.0×	0.006	AMN
Transport of small molecules	2	25.1×	0.006	AMN, ABCD1
Beta-oxidation of very long chain fatty acids	1	439.2×	0.006	ABCD1
Defects in cobalamin (B12) metabolism	1	407.9×	0.006	AMN
alpha-linolenic acid (ALA) metabolism	1	356.9×	0.006	ABCD1
Peroxisomal lipid metabolism	1	335.9×	0.006	ABCD1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.006	AMN
ABC transporters in lipid homeostasis	1	300.5×	0.006	ABCD1
Defects in vitamin and cofactor metabolism	1	300.5×	0.006	AMN
Class I peroxisomal membrane protein import	1	259.6×	0.007	ABCD1
Plasma lipoprotein clearance	1	237.9×	0.007	AMN
ABC transporter disorders	1	219.6×	0.007	ABCD1
Disease	2	13.1×	0.009	AMN, ABCD1
Metabolism	2	11.6×	0.011	AMN, ABCD1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.012	AMN
Protein localization	1	95.2×	0.014	ABCD1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.014	AMN
Disorders of transmembrane transporters	1	69.6×	0.017	ABCD1
Fatty acid metabolism	1	65.6×	0.018	ABCD1
ABC-family protein mediated transport	1	60.7×	0.018	ABCD1
Metabolism of vitamins and cofactors	1	58.3×	0.018	AMN
Diseases of metabolism	1	40.2×	0.026	AMN
Metabolism of lipids	1	15.8×	0.062	ABCD1

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
peroxisomal membrane transport	1	4213.0×	0.002	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	4213.0×	0.002	ABCD1
renal protein absorption	1	2808.7×	0.002	AMN
positive regulation of unsaturated fatty acid biosynthetic process	1	2808.7×	0.002	ABCD1
sterol homeostasis	1	2106.5×	0.002	ABCD1
long-chain fatty acid import into peroxisome	1	1685.2×	0.002	ABCD1
regulation of fatty acid beta-oxidation	1	1404.3×	0.002	ABCD1
long-chain fatty acid catabolic process	1	1404.3×	0.002	ABCD1
myelin maintenance	1	1404.3×	0.002	ABCD1
regulation of mitochondrial depolarization	1	1404.3×	0.002	ABCD1
fatty acid elongation	1	1203.7×	0.002	ABCD1
very long-chain fatty acid catabolic process	1	1203.7×	0.002	ABCD1
cobalamin transport	1	936.2×	0.003	AMN
cobalamin metabolic process	1	766.0×	0.003	AMN
positive regulation of fatty acid beta-oxidation	1	766.0×	0.003	ABCD1
fatty acid derivative biosynthetic process	1	766.0×	0.003	ABCD1
regulation of cellular response to oxidative stress	1	648.1×	0.003	ABCD1
regulation of oxidative phosphorylation	1	601.9×	0.003	ABCD1
neuron projection maintenance	1	561.7×	0.003	ABCD1
negative regulation of reactive oxygen species biosynthetic process	1	495.6×	0.003	ABCD1
fatty acid homeostasis	1	468.1×	0.003	ABCD1
alpha-linolenic acid metabolic process	1	443.5×	0.003	ABCD1
peroxisome organization	1	401.2×	0.003	ABCD1
very long-chain fatty acid metabolic process	1	383.0×	0.003	ABCD1
linoleic acid metabolic process	1	351.1×	0.004	ABCD1
unsaturated fatty acid biosynthetic process	1	324.1×	0.004	ABCD1
Golgi to plasma membrane protein transport	1	263.3×	0.004	AMN
long-chain fatty acid biosynthetic process	1	221.7×	0.005	ABCD1
negative regulation of cytokine production involved in inflammatory response	1	210.7×	0.005	ABCD1
fatty acid beta-oxidation	1	187.2×	0.006	ABCD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
AMN	0	0
ABCD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

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	1	ABCD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AMN

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)
AMN	0	—
ABCD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.