Familial hypobetalipoproteinemia 1

Summary

Familial hypobetalipoproteinemia 1 (MONDO:0014252) is a disease caused by APOB (GenCC Strong), with 1 cohort gene and 7 clinical trials. Top therapeutic interventions include mipomersen, tocofersolan, and alpha-tocopherol.

At a glance

• Causal gene: APOB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3,224
• Clinical trials: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypobetalipoproteinemia 1
Mondo ID	MONDO:0014252
MeSH	C566267
OMIM	615558
DOID	DOID:0111062
SNOMED CT	60193003
UMLS	C4551990
MedGen	1639219
GARD	0002876
Is cancer (heuristic)	no

Also known as: APOB hypobetalipoproteinemia · familial hypobetalipoproteinemia 1 · familial hypobetalipoproteinemia type 1 · FHBL · FHBL1 · hypobetalipoproteinemia · hypobetalipoproteinemia caused by mutation in APOB · hypobetalipoproteinemia, familial, 1 · hypobetalipoproteinemia, familial, type 1

Data availability: 3,224 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › familial hypobetalipoproteinemia 1

Related subtypes (3): abetalipoproteinemia, chylomicron retention disease, familial hypobetalipoproteinemia 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:

292 likely benign, 130 uncertain significance, 96 conflicting classifications of pathogenicity, 34 pathogenic, 18 benign/likely benign, 15 benign, 9 pathogenic/likely pathogenic, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068824	NM_000384.3(APOB):c.9615del (p.Asp3205fs)	APOB	Pathogenic	criteria provided, single submitter
1070406	NM_000384.3(APOB):c.7699C>T (p.Gln2567Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1070659	NM_000384.3(APOB):c.6403del (p.Val2135fs)	APOB	Pathogenic	criteria provided, single submitter
1071546	NM_000384.3(APOB):c.8594dup (p.Asn2865fs)	APOB	Pathogenic	criteria provided, single submitter
1174484	NM_000384.3(APOB):c.226_237+1del	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299572	NM_000384.3(APOB):c.1003del (p.Lys334_Leu335insTer)	APOB	Pathogenic	criteria provided, single submitter
1323319	NM_000384.3(APOB):c.3511G>T (p.Glu1171Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323322	NM_000384.3(APOB):c.1315C>T (p.Arg439Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1323325	NM_000384.3(APOB):c.11040T>G (p.Tyr3680Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330634	NM_000384.3(APOB):c.537+1G>T	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364654	NM_000384.3(APOB):c.8075_8076dup (p.Leu2693fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1369494	NM_000384.3(APOB):c.2979T>A (p.Tyr993Ter)	APOB	Pathogenic	criteria provided, single submitter
1386291	NM_000384.3(APOB):c.7489C>T (p.Gln2497Ter)	APOB	Pathogenic	criteria provided, single submitter
1402036	NM_000384.3(APOB):c.331_332del (p.Ala111fs)	APOB	Pathogenic	criteria provided, single submitter
1406951	NM_000384.3(APOB):c.9960del (p.Phe3320fs)	APOB	Pathogenic	criteria provided, single submitter
1416136	NM_000384.3(APOB):c.11532del (p.Asn3845fs)	APOB	Pathogenic	criteria provided, single submitter
1416940	NM_000384.3(APOB):c.1998C>A (p.Tyr666Ter)	APOB	Pathogenic	criteria provided, single submitter
1432825	NM_000384.3(APOB):c.11465del (p.Val3822fs)	APOB	Pathogenic	criteria provided, single submitter
1453164	NM_000384.3(APOB):c.7966_7969del (p.Phe2656fs)	APOB	Pathogenic	criteria provided, single submitter
1454956	NM_000384.3(APOB):c.10327G>T (p.Glu3443Ter)	APOB	Pathogenic	criteria provided, single submitter
1455782	NM_000384.3(APOB):c.8528_8531dup (p.Phe2845fs)	APOB	Pathogenic	criteria provided, single submitter
1456415	NM_000384.3(APOB):c.7704T>G (p.Tyr2568Ter)	APOB	Pathogenic	criteria provided, single submitter
1458005	NM_000384.3(APOB):c.3778G>T (p.Glu1260Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458186	NM_000384.3(APOB):c.1258G>T (p.Glu420Ter)	APOB	Pathogenic	criteria provided, single submitter
1678797	NM_000384.3(APOB):c.9632dup (p.Asn3211fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1705571	NM_000384.3(APOB):c.904+2T>C	APOB	Pathogenic	criteria provided, single submitter
17881	NM_000384.3(APOB):c.5263_5266del (p.Asn1755fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
17883	NM_000384.3(APOB):c.3997C>T (p.Arg1333Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
17884	NM_000384.3(APOB):c.5566_5567del (p.Val1856fs)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17887	NM_000384.3(APOB):c.6253C>T (p.Arg2085Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
APOB	Strong	Autosomal recessive	familial hypobetalipoproteinemia 1	9

Orphanet rare-disease linkage (cohort genes)

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

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
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom

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
ileal mucosa	1
jejunal mucosa	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOB	P04114	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. 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
Scavenging by Class H Receptors	1	2855.0×	0.004	APOB
VLDL assembly	1	2284.0×	0.004	APOB
Chylomicron clearance	1	2284.0×	0.004	APOB
Scavenging by Class F Receptors	1	1903.3×	0.004	APOB
LDL remodeling	1	1903.3×	0.004	APOB
VLDL clearance	1	1903.3×	0.004	APOB
Chylomicron assembly	1	1142.0×	0.004	APOB
Chylomicron remodeling	1	1142.0×	0.004	APOB
Scavenging by Class B Receptors	1	1038.2×	0.004	APOB
Plasma lipoprotein assembly	1	713.8×	0.005	APOB
Platelet sensitization by LDL	1	671.8×	0.005	APOB
Scavenging by Class A Receptors	1	601.0×	0.005	APOB
Binding and Uptake of Ligands by Scavenger Receptors	1	543.8×	0.005	APOB
LDL clearance	1	543.8×	0.005	APOB
Regulation of TLR by endogenous ligand	1	496.5×	0.005	APOB
Plasma lipoprotein remodeling	1	475.8×	0.005	APOB
Plasma lipoprotein clearance	1	475.8×	0.005	APOB
Metabolism of fat-soluble vitamins	1	380.7×	0.006	APOB
Platelet homeostasis	1	278.5×	0.008	APOB
Visual phototransduction	1	259.6×	0.008	APOB
Retinoid metabolism and transport	1	248.3×	0.008	APOB
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.008	APOB
Heme signaling	1	215.5×	0.008	APOB
Toll-like Receptor Cascades	1	124.1×	0.014	APOB
Metabolism of vitamins and cofactors	1	116.5×	0.014	APOB
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.015	APOB
Post-translational protein phosphorylation	1	100.2×	0.015	APOB
Cell surface interactions at the vascular wall	1	95.2×	0.015	APOB
Sensory Perception	1	95.2×	0.015	APOB
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.016	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
triglyceride mobilization	1	4213.0×	0.002	APOB
cellular response to lipoprotein particle stimulus	1	3370.4×	0.002	APOB
lipoprotein biosynthetic process	1	2808.7×	0.002	APOB
positive regulation of cholesterol storage	1	2407.4×	0.002	APOB
lipoprotein catabolic process	1	2407.4×	0.002	APOB
regulation of cholesterol biosynthetic process	1	1532.0×	0.002	APOB
positive regulation of lipid storage	1	1404.3×	0.002	APOB
very-low-density lipoprotein particle assembly	1	1203.7×	0.002	APOB
low-density lipoprotein particle remodeling	1	1053.2×	0.002	APOB
low-density lipoprotein particle clearance	1	991.3×	0.002	APOB
lipoprotein transport	1	991.3×	0.002	APOB
positive regulation of macrophage derived foam cell differentiation	1	842.6×	0.003	APOB
triglyceride catabolic process	1	802.5×	0.003	APOB
cholesterol transport	1	732.7×	0.003	APOB
artery morphogenesis	1	674.1×	0.003	APOB
cholesterol efflux	1	526.6×	0.003	APOB
fertilization	1	312.1×	0.005	APOB
post-embryonic development	1	205.5×	0.007	APOB
cholesterol metabolic process	1	195.9×	0.007	APOB
establishment of localization in cell	1	160.5×	0.008	APOB
cholesterol homeostasis	1	156.0×	0.008	APOB
response to virus	1	144.0×	0.009	APOB
flagellated sperm motility	1	117.0×	0.010	APOB
in utero embryonic development	1	72.0×	0.016	APOB
nervous system development	1	45.9×	0.024	APOB
positive regulation of gene expression	1	38.7×	0.027	APOB
spermatogenesis	1	35.2×	0.028	APOB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APOB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
APOB	1	Binding:1

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	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