Hereditary intrinsic factor deficiency

Summary

Hereditary intrinsic factor deficiency (MONDO:0009852) is a disease caused by CBLIF (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CBLIF (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 136
• Phenotypes (HPO): 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0005219	Absence of intrinsic factor	Obligate (100%)
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0100502	Decreased circulating vitamin B12 concentration	Very frequent (80-99%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002160	Hyperhomocystinemia	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002912	Methylmalonic acidemia	Frequent (30-79%)
HP:0025406	Asthenia	Frequent (30-79%)
HP:0200143	Megaloblastic erythroid hyperplasia	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0012120	Methylmalonic aciduria	Occasional (5-29%)
HP:6000344	Anti-intrinsic factor antibody positivity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary intrinsic factor deficiency
Mondo ID	MONDO:0009852
MeSH	C563242
OMIM	261000
Orphanet	332
DOID	DOID:0050734
SNOMED CT	34925000, 60504009
UMLS	C2062370
MedGen	1876474
GARD	0003024
MedDRA	10070440
Is cancer (heuristic)	no

Also known as: congenital intrinsic factor deficiency · congenital pernicious anaemia · congenital pernicious anaemia due to defect of intrinsic factor · congenital pernicious anemia · congenital pernicious anemia due to defect of intrinsic factor · gastric intrinsic factor deficiency · hereditary juvenile megaloblastic anaemia due to intrinsic factor deficiency · hereditary juvenile megaloblastic anemia due to intrinsic factor deficiency · IFD · intrinsic factor deficiency · intrinsic factor, congenital deficiency of

Data availability: 136 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › deficiency anemia › hereditary anemia › hereditary intrinsic factor deficiency

Related subtypes (13): microcytic anemia with liver iron overload, IRIDA syndrome, atransferrinemia, hereditary folate malabsorption, formiminoglutamic aciduria, Imerslund-Grasbeck syndrome, transcobalamin II deficiency, aceruloplasminemia, constitutional megaloblastic anemia with severe neurologic disease, severe congenital hypochromic anemia with ringed sideroblasts, methylmalonic aciduria and homocystinuria, homocystinuria without methylmalonic aciduria, vitamin B12- and folate-independent constitutional megaloblastic anemia

Subtypes (1): intrinsic factor and r binder, combined congenital deficiency of

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

136 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 48 likely benign, 11 conflicting classifications of pathogenicity, 9 pathogenic, 8 benign, 7 likely pathogenic, 3 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1745	NM_005142.3(CBLIF):c.80-1G>A	CBLIF	Pathogenic	no assertion criteria provided
1747	NM_005142.3(CBLIF):c.161del (p.Asn54fs)	CBLIF	Pathogenic	no assertion criteria provided
1748	NM_005142.3(CBLIF):c.1175dup (p.Thr393fs)	CBLIF	Pathogenic	no assertion criteria provided
208191	NM_005142.3(CBLIF):c.346C>T (p.Gln116Ter)	CBLIF	Pathogenic	criteria provided, single submitter
2903417	NM_005142.3(CBLIF):c.310C>T (p.Arg104Ter)	CBLIF	Pathogenic	criteria provided, single submitter
3721037	NM_005142.3(CBLIF):c.659T>C (p.Ile220Thr)	CBLIF	Pathogenic	criteria provided, single submitter
439755	NM_005142.3(CBLIF):c.79+1G>A	CBLIF	Pathogenic	criteria provided, multiple submitters, no conflicts
4749260	NM_005142.3(CBLIF):c.52_56del (p.Thr18fs)	CBLIF	Pathogenic	criteria provided, single submitter
566919	NM_005142.3(CBLIF):c.183_186del (p.Met61fs)	CBLIF	Pathogenic	criteria provided, multiple submitters, no conflicts
1746	NM_005142.3(CBLIF):c.137C>T (p.Ser46Leu)	CBLIF	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1969715	NM_005142.3(CBLIF):c.370+83_426del	CBLIF	Likely pathogenic	criteria provided, single submitter
2425302	NC_000011.9:g.(?59603261)(59604844_?)dup	CBLIF	Likely pathogenic	criteria provided, single submitter
2431712	NM_005142.3(CBLIF):c.370+1G>C	CBLIF	Likely pathogenic	criteria provided, single submitter
3362465	NM_005142.3(CBLIF):c.395_396delinsAA (p.Phe132Ter)	CBLIF	Likely pathogenic	criteria provided, single submitter
3766532	NM_005142.3(CBLIF):c.67_68del (p.Gln23fs)	CBLIF	Likely pathogenic	criteria provided, single submitter
830018	NM_005142.3(CBLIF):c.661G>A (p.Gly221Arg)	CBLIF	Likely pathogenic	no assertion criteria provided
2085122	NM_005142.3(CBLIF):c.749C>T (p.Thr250Met)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305032	NM_005142.3(CBLIF):c.910C>T (p.Pro304Ser)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305037	NM_005142.3(CBLIF):c.455C>T (p.Pro152Leu)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305038	NM_005142.3(CBLIF):c.379G>A (p.Ala127Thr)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305040	NM_005142.3(CBLIF):c.290T>C (p.Met97Thr)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305044	NM_005142.3(CBLIF):c.154T>A (p.Tyr52Asn)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574163	NM_005142.3(CBLIF):c.1163T>C (p.Phe388Ser)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
660115	NM_005142.3(CBLIF):c.829G>C (p.Gly277Arg)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719724	NM_005142.3(CBLIF):c.256+10C>T	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
761936	NM_005142.3(CBLIF):c.138G>A (p.Ser46=)	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800190	NM_005142.3(CBLIF):c.1074-3T>C	CBLIF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005545	NM_005142.3(CBLIF):c.1064C>G (p.Pro355Arg)	CBLIF	Uncertain significance	criteria provided, single submitter
1008760	NM_005142.3(CBLIF):c.1190A>T (p.Glu397Val)	CBLIF	Uncertain significance	criteria provided, single submitter
1038547	NM_005142.3(CBLIF):c.446C>A (p.Ala149Glu)	CBLIF	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
CBLIF	Strong	Autosomal recessive	hereditary intrinsic factor deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CBLIF	Orphanet:332	Congenital intrinsic factor deficiency

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
CBLIF	HGNC:4268	ENSG00000134812	P27352	Cobalamin binding intrinsic factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CBLIF	Cobalamin binding intrinsic factor	Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum.

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)
CBLIF	Other/Unknown	no		Cbl-bd_prot, Cobalamin_Transport

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
body of stomach	1
cardia of stomach	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CBLIF	141	tissue_specific	marker	cardia of stomach, pylorus, body of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CBLIF	495

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBLIF	P27352	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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 CBLIF causes IFD	1	11420.0×	4e-04	CBLIF
Defective AMN causes MGA1	1	3806.7×	4e-04	CBLIF
Defective CUBN causes MGA1	1	3806.7×	4e-04	CBLIF
Uptake of dietary cobalamins into enterocytes	1	1142.0×	9e-04	CBLIF

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
cobalt ion transport	1	2407.4×	5e-04	CBLIF
cobalamin transport	1	1872.4×	5e-04	CBLIF

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
CBLIF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	CBLIF

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)
CBLIF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns