Hypobetalipoproteinemia

Summary

Hypobetalipoproteinemia (MONDO:0017774) is a disease with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include mipomersen, tocofersolan, and alpha-tocopherol.

At a glance

• Cohort genes: 2
• ClinVar variants: 114
• Clinical trials: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypobetalipoproteinemia
Mondo ID	MONDO:0017774
MeSH	D006995
Orphanet	31154
DOID	DOID:1390
ICD-11	1934975006
SNOMED CT	190786004
UMLS	C0020597
MedGen	6978
GARD	0018802
Is cancer (heuristic)	no

Data availability: 114 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › hypolipoproteinemia › hypobetalipoproteinemia

Related subtypes (2): Tangier disease, Norum disease

Subtypes (4): abetalipoproteinemia, chylomicron retention disease, familial hypobetalipoproteinemia 2, familial hypobetalipoproteinemia 1

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

114 retrieved; paginated sample, class counts are floors:

42 conflicting classifications of pathogenicity, 30 uncertain significance, 16 benign/likely benign, 12 benign, 7 likely pathogenic, 4 pathogenic/likely pathogenic, 2 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458005	NM_000384.3(APOB):c.3778G>T (p.Glu1260Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17890	NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2044989	NM_000384.3(APOB):c.8739_8740del (p.Leu2914fs)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434252	NM_000384.3(APOB):c.10238del (p.Thr3413fs)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
895430	NM_000384.3(APOB):c.7600C>T (p.Arg2534Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
210222	NM_000384.3(APOB):c.13025del (p.Pro4342fs)	APOB	Likely pathogenic	criteria provided, single submitter
228245	NM_000384.3(APOB):c.631C>T (p.Gln211Ter)	APOB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582602	NM_000384.3(APOB):c.78_82+5del	APOB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3076010	NM_000384.3(APOB):c.8898dup (p.His2967fs)	APOB	Likely pathogenic	criteria provided, single submitter
3076012	NM_000384.3(APOB):c.4139_4140del (p.Thr1380fs)	APOB	Likely pathogenic	criteria provided, single submitter
374255	NM_000384.3(APOB):c.2988_2994del (p.Gly997fs)	APOB	Likely pathogenic	criteria provided, single submitter
434251	NM_000384.3(APOB):c.11812_11813del (p.Asp3938fs)	APOB	Likely pathogenic	criteria provided, single submitter
201128	NM_174936.4(PCSK9):c.1405C>T (p.Arg469Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201129	NM_174936.4(PCSK9):c.1486C>T (p.Arg496Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242028	NM_174936.4(PCSK9):c.720C>T (p.Gly240=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262899	NM_174936.4(PCSK9):c.1026A>G (p.Gln342=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262902	NM_174936.4(PCSK9):c.141C>T (p.Ser47=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262906	NM_174936.4(PCSK9):c.657+9G>A	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262907	NM_174936.4(PCSK9):c.753C>T (p.Arg251=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265912	NM_174936.4(PCSK9):c.-245G>T	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265932	NM_174936.4(PCSK9):c.705C>T (p.Ser235=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265933	NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265944	NM_174936.4(PCSK9):c.1399C>G (p.Pro467Ala)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265950	NM_174936.4(PCSK9):c.*75C>T	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297685	NM_174936.4(PCSK9):c.-245G>C	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297693	NM_174936.4(PCSK9):c.168C>T (p.Pro56=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297694	NM_174936.4(PCSK9):c.399+4A>G	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297702	NM_174936.4(PCSK9):c.1332G>A (p.Leu444=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297704	NM_174936.4(PCSK9):c.1954A>G (p.Asn652Asp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297709	NM_174936.4(PCSK9):c.2022C>T (p.Ala674=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCSK9	Orphanet:391665	Homozygous familial hypercholesterolemia
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia

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
PCSK9	HGNC:20001	ENSG00000169174	Q8NBP7	Proprotein convertase subtilisin/kexin type 9	clinvar
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCSK9	Proprotein convertase subtilisin/kexin type 9	Crucial player in the regulation of plasma cholesterol homeostasis.
APOB	Apolipoprotein B-100	Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100).

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCSK9	Protease	yes	3.4.21.61	Peptidase_S8/S53_dom, S8pro/Inhibitor_I9, Peptidase_S8_subtilisin-rel
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom

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
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
right lobe of liver	1
ileal mucosa	1
jejunal mucosa	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCSK9	147	broad	marker	right lobe of liver, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244
PCSK9	2,994

Intra-cohort edges

A	B	Sources
APOB	PCSK9	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCSK9	Q8NBP7	65
APOB	P04114	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. 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
LDL clearance	2	543.8×	1e-04	PCSK9, APOB
Post-translational protein phosphorylation	2	100.2×	0.002	PCSK9, APOB
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	86.5×	0.002	PCSK9, APOB
Scavenging by Class H Receptors	1	1427.5×	0.005	APOB
VLDL assembly	1	1142.0×	0.005	APOB
Chylomicron clearance	1	1142.0×	0.005	APOB
Scavenging by Class F Receptors	1	951.7×	0.005	APOB
LDL remodeling	1	951.7×	0.005	APOB
VLDL clearance	1	951.7×	0.005	APOB
Chylomicron assembly	1	571.0×	0.007	APOB
Chylomicron remodeling	1	571.0×	0.007	APOB
Scavenging by Class B Receptors	1	519.1×	0.007	APOB
VLDLR internalisation and degradation	1	356.9×	0.009	PCSK9
Plasma lipoprotein assembly	1	356.9×	0.009	APOB
Platelet sensitization by LDL	1	335.9×	0.009	APOB
Scavenging by Class A Receptors	1	300.5×	0.009	APOB
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.009	APOB
Regulation of TLR by endogenous ligand	1	248.3×	0.009	APOB
Plasma lipoprotein remodeling	1	237.9×	0.009	APOB
Plasma lipoprotein clearance	1	237.9×	0.009	APOB
Metabolism of fat-soluble vitamins	1	190.3×	0.011	APOB
Platelet homeostasis	1	139.3×	0.014	APOB
Visual phototransduction	1	129.8×	0.014	APOB
Retinoid metabolism and transport	1	124.1×	0.014	APOB
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.015	APOB
Heme signaling	1	107.7×	0.015	APOB
Toll-like Receptor Cascades	1	62.1×	0.026	APOB
Metabolism of vitamins and cofactors	1	58.3×	0.026	APOB
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.028	APOB
Cell surface interactions at the vascular wall	1	47.6×	0.029	APOB

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
cholesterol metabolic process	2	195.9×	1e-03	PCSK9, APOB
cholesterol homeostasis	2	156.0×	1e-03	PCSK9, APOB
low-density lipoprotein particle receptor catabolic process	1	8426.0×	0.002	PCSK9
negative regulation of sodium ion import across plasma membrane	1	4213.0×	0.002	PCSK9
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	4213.0×	0.002	PCSK9
positive regulation of low-density lipoprotein particle receptor catabolic process	1	2808.7×	0.003	PCSK9
triglyceride mobilization	1	2106.5×	0.003	APOB
negative regulation of receptor recycling	1	1685.2×	0.003	PCSK9
cellular response to lipoprotein particle stimulus	1	1685.2×	0.003	APOB
lipoprotein biosynthetic process	1	1404.3×	0.003	APOB
positive regulation of cholesterol storage	1	1203.7×	0.003	APOB
lipoprotein catabolic process	1	1203.7×	0.003	APOB
negative regulation of low-density lipoprotein particle clearance	1	766.0×	0.005	PCSK9
regulation of cholesterol biosynthetic process	1	766.0×	0.005	APOB
positive regulation of lipid storage	1	702.2×	0.005	APOB
negative regulation of receptor internalization	1	601.9×	0.005	PCSK9
very-low-density lipoprotein particle assembly	1	601.9×	0.005	APOB
low-density lipoprotein particle remodeling	1	526.6×	0.005	APOB
low-density lipoprotein particle clearance	1	495.6×	0.005	APOB
lipoprotein transport	1	495.6×	0.005	APOB
lipoprotein metabolic process	1	468.1×	0.005	PCSK9
positive regulation of macrophage derived foam cell differentiation	1	421.3×	0.005	APOB
triglyceride catabolic process	1	401.2×	0.005	APOB
cholesterol transport	1	366.4×	0.005	APOB
positive regulation of receptor internalization	1	351.1×	0.005	PCSK9
lysosomal transport	1	351.1×	0.005	PCSK9
regulation of neuron apoptotic process	1	351.1×	0.005	PCSK9
artery morphogenesis	1	337.0×	0.005	APOB
protein autoprocessing	1	324.1×	0.005	PCSK9
cholesterol efflux	1	263.3×	0.006	APOB

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

2 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Tocofersolan	Phase 3
Vitamin E	Phase 3

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PCSK9	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCSK9	1	4
APOB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	PCSK9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PCSK9	202	Binding:201, ADMET:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCSK9	3.4.21.61	Kexin

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PCSK9	202

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
NILOTINIB	4	PCSK9

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PCSK9
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	APOB

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)
APOB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01457690	PHASE3	COMPLETED	Study of the Absorption of Vitamin E Water-soluble Form (Pegylated) in the Familial Hypocholesterolemia With Chylomicron Retention
NCT00362180	PHASE2	COMPLETED	Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration
NCT02354079	Not specified	ACTIVE_NOT_RECRUITING	HYPOCHOL : A Genetically-based Strategy to Identify New Targets in Cholesterol Metabolism
NCT00005565	Not specified	COMPLETED	Mechanisms of Low Levels of Apolipoprotein B
NCT02889614	Not specified	COMPLETED	Prevalence Assessment and Characterization of Psychological Disorders Associated With Hypobetalipoproteinemia
NCT03549637	Not specified	COMPLETED	Prevalence of fAmilial hypobetalipopRoTeinemIa in psychiaTrIc pOpulatioN (PARTITION)
NCT05569928	Not specified	UNKNOWN	In Vivo Metabolism of apoB-containing Lipoproteins in ANGPTL3 Deficient Subjects

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIPOMERSEN	4	2
TOCOFERSOLAN	4	1
ALPHA-TOCOPHEROL	0	1