Imerslund-Grasbeck syndrome

Summary

Imerslund-Grasbeck syndrome (MONDO:0009853) is a disease with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 1,920
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.5	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.5	Finland	Validated
Point prevalence	1-9 / 1 000 000	0.5	Norway	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0100502	Decreased circulating vitamin B12 concentration	Obligate (100%)
HP:0200118	Malabsorption of Vitamin B12	Obligate (100%)
HP:0410216	Abnormal blood 5-methyltetrahydrofolate level	Obligate (100%)
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0001972	Macrocytic anemia	Very frequent (80-99%)
HP:0004821	Hypersegmentation of neutrophil nuclei	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0004823	Anisopoikilocytosis	Frequent (30-79%)
HP:0020061	Abnormal hemoglobin concentration	Frequent (30-79%)
HP:0032566	Oval macrocytosis	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0000206	Glossitis	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0030318	Angular cheilitis	Occasional (5-29%)
HP:0031936	Delayed ability to walk	Occasional (5-29%)
HP:0002721	Immunodeficiency	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Imerslund-Grasbeck syndrome
Mondo ID	MONDO:0009853
MeSH	C538556
OMIM	261100
Orphanet	35858
ICD-11	375969525
SNOMED CT	360495000
UMLS	C4551825
MedGen	1640347
GARD	0007006
Is cancer (heuristic)	no

Also known as: defect of enterocyte intrinsic factor receptor · familial megaloblastic anaemia · familial megaloblastic anemia · Imerslund-Grasbeck syndrome · Imerslund-Gräsbeck syndrome · juvenile megaloblastic Anaemia · juvenile megaloblastic Anemia · selective cobalamin malabsorption with proteinuria

Data availability: 1,920 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (5): pernicious anemia, hereditary folate malabsorption, formiminoglutamic aciduria, constitutional megaloblastic anemia with severe neurologic disease, vitamin B12- and folate-independent constitutional megaloblastic anemia

Subtypes (2): Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2

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

600 retrieved; paginated sample, class counts are floors:

289 uncertain significance, 236 likely benign, 21 conflicting classifications of pathogenicity, 15 benign/likely benign, 12 pathogenic, 12 benign, 7 pathogenic/likely pathogenic, 7 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033271	NM_001081.4(CUBN):c.4165del (p.Tyr1389fs)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072126	NM_001081.4(CUBN):c.7013del (p.Gly2338fs)	CUBN	Pathogenic	criteria provided, single submitter
1074937	NM_001081.4(CUBN):c.10462C>T (p.Arg3488Ter)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074985	NM_001081.4(CUBN):c.7051G>T (p.Gly2351Ter)	CUBN	Pathogenic	criteria provided, single submitter
1075676	NM_001081.4(CUBN):c.2191_2192del (p.Thr731fs)	CUBN	Pathogenic	criteria provided, single submitter
1076401	NM_001081.4(CUBN):c.1892del (p.Thr631fs)	CUBN	Pathogenic	criteria provided, single submitter
1179172	NM_001081.4(CUBN):c.8755C>T (p.Arg2919Ter)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179174	NM_001081.4(CUBN):c.8463G>A (p.Trp2821Ter)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322175	NM_001081.4(CUBN):c.10612G>T (p.Glu3538Ter)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322176	NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter)	CUBN	Pathogenic	criteria provided, multiple submitters, no conflicts
1427549	NM_001081.4(CUBN):c.8684_8687del (p.Ser2895fs)	CUBN	Pathogenic	criteria provided, single submitter
1444492	NM_001081.4(CUBN):c.424C>T (p.Gln142Ter)	CUBN	Pathogenic	criteria provided, single submitter
1444519	NM_001081.4(CUBN):c.7802G>A (p.Trp2601Ter)	CUBN	Pathogenic	criteria provided, single submitter
189227	NM_001081.4(CUBN):c.6928_6934del (p.Glu2310fs)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1992848	NM_001081.4(CUBN):c.9783del (p.Thr3261_Leu3262insTer)	CUBN	Pathogenic	criteria provided, single submitter
2009822	NM_001081.4(CUBN):c.8049del (p.Lys2683fs)	CUBN	Pathogenic	criteria provided, single submitter
2032699	NM_001081.4(CUBN):c.5701G>T (p.Glu1901Ter)	CUBN	Pathogenic	criteria provided, single submitter
2104999	NM_001081.4(CUBN):c.794dup (p.Asp265fs)	CUBN	Pathogenic	criteria provided, single submitter
2147526	NM_001081.4(CUBN):c.8126_8127del (p.Ala2708_Tyr2709insTer)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066455	NM_001081.4(CUBN):c.7001-2del	CUBN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328629	NM_001081.4(CUBN):c.4350+2T>C	CUBN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1348969	NM_001081.4(CUBN):c.3008+2_3008+5del	CUBN	Likely pathogenic	criteria provided, single submitter
1495871	NM_001081.4(CUBN):c.4856-1del	CUBN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2109136	NM_001081.4(CUBN):c.4969+2T>G	CUBN	Likely pathogenic	criteria provided, single submitter
2142928	NM_001081.4(CUBN):c.6822-1G>A	CUBN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2146199	NM_001081.4(CUBN):c.8063-1G>A	CUBN	Likely pathogenic	criteria provided, single submitter
1022286	NM_030943.4(AMN):c.1343G>A (p.Gly448Glu)	AMN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2042982	NM_030943.4(AMN):c.892T>C (p.Ser298Pro)	AMN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016175	NM_001081.4(CUBN):c.10028C>T (p.Pro3343Leu)	CUBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022289	NM_001081.4(CUBN):c.6821+2T>C	CUBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 8 · 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
CUBN	Definitive	Autosomal recessive	Imerslund-Grasbeck syndrome type 1	5
ABCD1	Strong	Autosomal recessive	Imerslund-Grasbeck syndrome type 1	11
AMN	Strong	Autosomal recessive	Imerslund-Grasbeck syndrome type 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMN	Orphanet:35858	Imerslund-Gräsbeck syndrome
CUBN	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
VIM	Orphanet:675396	Epithelioid hemangioma
VIM	Orphanet:98984	Pulverulent cataract

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AMN	HGNC:14604	ENSG00000166126	Q9BXJ7	Protein amnionless	gencc,clinvar
CUBN	HGNC:2548	ENSG00000107611	O60494	Cubilin	gencc,clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	gencc,clinvar
VIM	HGNC:12692	ENSG00000026025	P08670	Vimentin	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.
CUBN	Cubilin	Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake.
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.
VIM	Vimentin	Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	19.4×	0.101
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMN	Other/Unknown	no		AMN
CUBN	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
VIM	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
jejunal mucosa	1
mucosa of transverse colon	1
adult organism	1
kidney epithelium	1
nephron tubule	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
descending thoracic aorta	1
right coronary artery	1
ventricular zone	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
CUBN	188	broad	marker	adult organism, nephron tubule, kidney epithelium
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
VIM	307	ubiquitous	marker	ventricular zone, descending thoracic aorta, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VIM	6,814
CUBN	1,193
ABCD1	1,181
AMN	414

Intra-cohort edges

A	B	Sources
AMN	CUBN	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VIM	P08670	26
ABCD1	P33897	14
CUBN	O60494	2
AMN	Q9BXJ7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective AMN causes MGA1	2	1903.3×	6e-06	AMN, CUBN
Defective CUBN causes MGA1	2	1903.3×	6e-06	AMN, CUBN
HDL clearance	2	1142.0×	1e-05	AMN, CUBN
Uptake of dietary cobalamins into enterocytes	2	571.0×	4e-05	AMN, CUBN
Defective ABCD1 causes ALD	1	1427.5×	0.006	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	475.8×	0.014	ABCD1
Linoleic acid (LA) metabolism	1	285.5×	0.016	ABCD1
Caspase-mediated cleavage of cytoskeletal proteins	1	237.9×	0.016	VIM
Vitamin D (calciferol) metabolism	1	219.6×	0.016	CUBN
Beta-oxidation of very long chain fatty acids	1	219.6×	0.016	ABCD1
Defects in cobalamin (B12) metabolism	1	203.9×	0.016	AMN
alpha-linolenic acid (ALA) metabolism	1	178.4×	0.016	ABCD1
Peroxisomal lipid metabolism	1	167.9×	0.016	ABCD1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	158.6×	0.016	AMN
ABC transporters in lipid homeostasis	1	150.3×	0.016	ABCD1
Defects in vitamin and cofactor metabolism	1	150.3×	0.016	AMN
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	135.9×	0.016	VIM
Class I peroxisomal membrane protein import	1	129.8×	0.016	ABCD1
Chaperone Mediated Autophagy	1	124.1×	0.016	VIM
Plasma lipoprotein clearance	1	119.0×	0.016	AMN
RHOBTB1 GTPase cycle	1	119.0×	0.016	VIM
ABC transporter disorders	1	109.8×	0.016	ABCD1
Transport of small molecules	2	12.6×	0.016	AMN, ABCD1
Late endosomal microautophagy	1	81.6×	0.020	VIM
Dengue Virus Genome Translation and Replication	1	79.3×	0.020	VIM
Striated Muscle Contraction	1	77.2×	0.020	VIM
Aggrephagy	1	62.1×	0.024	VIM
Plasma lipoprotein assembly, remodeling, and clearance	1	57.1×	0.025	AMN
Protein localization	1	47.6×	0.029	ABCD1
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.029	AMN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cobalamin transport	2	936.2×	6e-05	AMN, CUBN
cobalamin metabolic process	2	766.0×	6e-05	AMN, CUBN
receptor-mediated endocytosis	2	110.9×	0.002	AMN, CUBN
peroxisomal membrane transport	1	2106.5×	0.005	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	2106.5×	0.005	ABCD1
renal protein absorption	1	1404.3×	0.005	AMN
positive regulation of unsaturated fatty acid biosynthetic process	1	1404.3×	0.005	ABCD1
sterol homeostasis	1	1053.2×	0.005	ABCD1
long-chain fatty acid import into peroxisome	1	842.6×	0.005	ABCD1
regulation of fatty acid beta-oxidation	1	702.2×	0.005	ABCD1
long-chain fatty acid catabolic process	1	702.2×	0.005	ABCD1
myelin maintenance	1	702.2×	0.005	ABCD1
regulation of mitochondrial depolarization	1	702.2×	0.005	ABCD1
fatty acid elongation	1	601.9×	0.005	ABCD1
very long-chain fatty acid catabolic process	1	601.9×	0.005	ABCD1
lens fiber cell development	1	526.6×	0.006	VIM
cellular response to muramyl dipeptide	1	421.3×	0.006	VIM
positive regulation of fatty acid beta-oxidation	1	383.0×	0.006	ABCD1
Bergmann glial cell differentiation	1	383.0×	0.006	VIM
fatty acid derivative biosynthetic process	1	383.0×	0.006	ABCD1
regulation of cellular response to oxidative stress	1	324.1×	0.007	ABCD1
regulation of oxidative phosphorylation	1	300.9×	0.007	ABCD1
astrocyte development	1	280.9×	0.007	VIM
neuron projection maintenance	1	280.9×	0.007	ABCD1
lipoprotein transport	1	247.8×	0.008	CUBN
negative regulation of reactive oxygen species biosynthetic process	1	247.8×	0.008	ABCD1
fatty acid homeostasis	1	234.1×	0.008	ABCD1
alpha-linolenic acid metabolic process	1	221.7×	0.008	ABCD1
peroxisome organization	1	200.6×	0.008	ABCD1
very long-chain fatty acid metabolic process	1	191.5×	0.009	ABCD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
CUBN	0	0
ABCD1	0	0
VIM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VIM	18	Binding:18

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: 4; 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	3	AMN, CUBN, VIM

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMN	0	—
CUBN	0	—
ABCD1	0	—
VIM	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.