vitamin B12 deficiency

Summary

vitamin B12 deficiency (MONDO:0020696) is a disease with 2 cohort genes (17 GWAS associations across 15 studies) and 20 clinical trials. Top therapeutic interventions include cyanocobalamin, folic acid, and hydroxocobalamin.

At a glance

• Cohort genes: 2
• GWAS associations: 17
• ClinVar variants: 2
• Clinical trials: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin B12 deficiency
Mondo ID	MONDO:0020696
EFO	EFO:0000734
MeSH	D014806
ICD-11	1366882206
NCIT	C131684
SNOMED CT	190634004
UMLS	C0042847
MedGen	21880
Is cancer (heuristic)	no

Also known as: cobalamin deficiency · hypocobalaminemia · vitamin b12 deficiency

Data availability: 2 ClinVar variants · 17 GWAS associations (15 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › vitamin B12 deficiency

Related subtypes (36): glutaric aciduria, mineral metabolism disease, xanthinuria, chondrocalcinosis, ochronosis disorder, glucose metabolism disease, diabetic kidney disease, xanthoma, diabetic retinopathy, hypertriglyceridemia, gout, lactic acidosis, acquired metabolic disease, lipodystrophy, developmental anomaly of metabolic origin, dopa-responsive dystonia, hypoalphalipoproteinemia, steroid dehydrogenase deficiency-dental anomalies syndrome, inborn errors of metabolism, proteostasis deficiencies, hyperlipidemia, disorder of GPI anchor biosynthesis, bilirubin metabolism disease, hyperlipoproteinemia, carbohydrate metabolism disease, porphyrin metabolism disease, purine metabolism disease, amino acid metabolism disease, pyrimidine metabolism disease, disorder of acid-base balance, disorder of glutamate decarboxylase, tumor lysis syndrome, collagenous sprue, steroid metabolism disease, disorder of organic acid metabolism, skeletal fluorosis

Subtypes (1): inborn disorder of cobalamin metabolism and transport

Genetics & variants

GWAS landscape

17 GWAS associations across 15 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs503644	1e-72	TCN1 - OOSP3	T	0.98
rs34324219	6e-62	TCN1	C	0.32
rs1801222	1e-50	CUBN	A	0.19
rs679574	6e-45	FUT2	C	0.17
rs601338	5e-34	FUT2	G	0.16
rs1131603	5e-25	TCN2	T	0.36
rs73425947	1e-22	EEF1A1P42 - MMUT	G	0.12
chr6:49450370	3e-19		C	0.12
rs2232775	4e-19	CD320	T	0.2
chr19:48703346	2e-18		?	0.23
chr19:5839746	1e-14		G	0.21
rs10409772	1e-14	FUT6 - FUT3	C	0.14
rs116075662	2e-12	MMAA	G	0.18
chr19:49206145	2e-11		G	0.18

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475776	Verma A	2024	12,074	430,118	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90727294	Kim HI	2026	3,037	40,989	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90475775	Verma A	2024	2,807	117,071	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479962	Verma A	2024	2,807	117,071	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477450	Verma A	2024	1,387	57,503	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90079706	Backman JD	2021	1,370	385,838	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083692	Backman JD	2021	1,370	385,838	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90297592	Auwerx C	2024	1,257	300,091	Rare copy-number variants as modulators of common disease susceptibility.
GCST90297646	Auwerx C	2024	1,257	300,091	Rare copy-number variants as modulators of common disease susceptibility.
GCST90297696	Auwerx C	2024	1,257	300,091	Rare copy-number variants as modulators of common disease susceptibility.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	5
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	8

MAF distribution

Bucket	Variants
common (>=0.05)	10
low_freq (0.01-0.05)	3
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
missense_variant	4
unknown	4
intergenic_variant	2
intron_variant	2
stop_gained	1
splice_polypyrimidine_tract_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs503644	11	59873981	T>A,C	0.022	intergenic_variant	TCN1 - OOSP3	1e-72	Tier 4: intronic/intergenic
rs34324219	11	59855905	C>A	0.113	missense_variant	TCN1	6e-62	Tier 1: coding
rs1801222	10	17114152	A>C,G,T	0.304	missense_variant	CUBN	1e-50	Tier 1: coding
rs679574	19	48702851	C>A,G	0.475	intron_variant	FUT2	6e-45	Tier 4: intronic/intergenic
rs601338	19	48703417	G>A	0.488	stop_gained	FUT2	5e-34	Tier 1: coding
rs1131603	22	30622988	T>C	0.04	missense_variant	TCN2	5e-25	Tier 1: coding
rs73425947	6	49393404	G>T	0.32	splice_polypyrimidine_tract_variant	EEF1A1P42 - MMUT	1e-22	Tier 2: splice/UTR
chr6:49450370				0.401			3e-19	Tier 4: intronic/intergenic
rs2232775	19	8308268	T>A,C	0.114	missense_variant	CD320	4e-19	Tier 1: coding
chr19:48703346							2e-18	Tier 4: intronic/intergenic
chr19:5839746				0.481			1e-14	Tier 4: intronic/intergenic
rs10409772	19	5840915	C>A,G,T	0.185	intergenic_variant	FUT6 - FUT3	1e-14	Tier 4: intronic/intergenic
rs116075662	4	145653003	G>A	0.048	intron_variant	MMAA	2e-12	Tier 4: intronic/intergenic
chr19:49206145				0.496			2e-11	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

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cyanocobalamin, Mecobalamin.

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: 20.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	15
PHASE4	3
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07029698	PHASE4	RECRUITING	A Study to See if a Combination of Vitamins That is Injected Into a Muscle is as Good and Safe as a Vitamin That is Taken by Mouth
NCT00326833	PHASE4	UNKNOWN	How Many Patients Are in Need of Vitamin B12 Injections?
NCT02270749	PHASE4	COMPLETED	Vitamin Deficiencies and Suppletion in Morbid Obesity
NCT00279552	PHASE2	COMPLETED	Can Recombinant Human Intrinsic Factor Be Used for Evaluation of the Vitamin B12 Absorption?
NCT00699478	PHASE2	COMPLETED	Oral Vitamin B12 Administration for Vitamin B12 Deficiency After Total Gastrectomy
NCT06528366	Not specified	ACTIVE_NOT_RECRUITING	Heart Failure With Reduced Ejection Fraction: Adjuvant Therapy With Neurostimulation and Chlorella Pyrenoidosa (HD-tDCS)
NCT00467623	Not specified	COMPLETED	Holotranscobalamin Remains Unchanged During Pregnancy
NCT00826657	Not specified	COMPLETED	Vitamin B12 Supplementation Study
NCT00843453	Not specified	COMPLETED	Long-term Use of Proton Pump Inhibitors May Cause Vitamin B12 Deficiency in the Institutionalized Elderly
NCT01136512	Not specified	COMPLETED	Metformin Use and Vitamin B12 Deficiency
NCT01297361	Not specified	COMPLETED	The Association Between Religious Origin and Age, and Vitamin B12 and Folic Acid Plasma Levels in Non Jewish Population in Western Galilee
NCT01584050	Not specified	COMPLETED	Relative Bioavailability of Folic Acid and L-5-Methlytetrahydrofolate
NCT01661309	Not specified	COMPLETED	Supplementary Vitamin B12 Effects on Elevated Homocysteine Levels of Vegetarians - Clinical Trial
NCT01876329	Not specified	COMPLETED	Autoantibodies to Gastric Parietal Cells in Rheumatoid Arthritis Patients
NCT01876732	Not specified	COMPLETED	Impact of Vitamin B12 Replacement on Epogen Dosing and Improvement of Quality of Life in Hemodialysis Patients
NCT02076347	Not specified	COMPLETED	Comparison of Two Pharmacist-led Population Management Approaches to Increase Monitoring of Vitamin B12 and Serum Creatinine Levels for Patients on Metformin
NCT02540642	Not specified	COMPLETED	Effect of Vitamin B12 Supplementation on Glycaemic Control in Uncontrolled Hyperhomocysteinemic Type 2 Diabetic Patients
NCT02679833	Not specified	COMPLETED	Effect of Toothpaste Fortified With Cyanocobalamin on Vitamin B12 Status
NCT04048330	Not specified	UNKNOWN	Periconceptional Surveillance in India
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYANOCOBALAMIN	4	5
FOLIC ACID	4	2
HYDROXOCOBALAMIN	4	1
MECOBALAMIN	4	1
PYRIDOXINE	4	1
METHYLCOBALAMIN	2	3
CHEMBL4303681	0	4
VITAMIN B12	0	4