Familial hypobetalipoproteinemia 2

Summary

Familial hypobetalipoproteinemia 2 (MONDO:0011505) is a disease caused by ANGPTL3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ANGPTL3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypobetalipoproteinemia 2
Mondo ID	MONDO:0011505
MeSH	C565732
OMIM	605019
DOID	DOID:0111061
UMLS	C1857970
MedGen	341895
GARD	0015376
Is cancer (heuristic)	no

Also known as: ANGPTL3 hypobetalipoproteinemia · familial hypobetalipoproteinemia 2 · familial hypobetalipoproteinemia type 2 · FHBL2 · hypobetalipoproteinemia caused by mutation in ANGPTL3 · hypobetalipoproteinemia, familial, 2 · hypobetalipoproteinemia, familial, type 2

Data availability: 12 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 2

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

12 retrieved; paginated sample, class counts are floors:

6 pathogenic, 2 conflicting classifications of pathogenicity, 2 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18439	NM_014495.4(ANGPTL3):c.50_51delinsGA (p.Ser17Ter)	ANGPTL3	Pathogenic	no assertion criteria provided
18440	NM_014495.4(ANGPTL3):c.385G>T (p.Glu129Ter)	ANGPTL3	Pathogenic	no assertion criteria provided
91863	NM_014495.4(ANGPTL3):c.1198+1G>T	ANGPTL3	Pathogenic	no assertion criteria provided
91864	NM_014495.4(ANGPTL3):c.55del (p.Ile19fs)	ANGPTL3	Pathogenic	no assertion criteria provided
91865	NM_014495.4(ANGPTL3):c.439_442del (p.Thr146_Asn147insTer)	ANGPTL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
91866	NM_014495.4(ANGPTL3):c.363_367del (p.Asn121fs)	ANGPTL3	Pathogenic	criteria provided, multiple submitters, no conflicts
91867	NM_014495.4(ANGPTL3):c.883T>C (p.Phe295Leu)	ANGPTL3	Pathogenic	no assertion criteria provided
4845847	NM_014495.4(ANGPTL3):c.372del (p.Glu125fs)	ANGPTL3	Likely pathogenic	criteria provided, single submitter
1580782	NM_014495.4(ANGPTL3):c.1028A>G (p.His343Arg)	ANGPTL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803843	NM_014495.4(ANGPTL3):c.956A>G (p.Lys319Arg)	ANGPTL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803867	NM_014495.4(ANGPTL3):c.995G>A (p.Arg332Gln)	ANGPTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439036	NM_014495.4(ANGPTL3):c.280GAA[2] (p.Glu96del)	ANGPTL3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
ANGPTL3	Strong	Autosomal recessive	familial hypobetalipoproteinemia 2	3

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
ANGPTL3	HGNC:491	ENSG00000132855	Q9Y5C1	Angiopoietin-related protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANGPTL3	Angiopoietin-related protein 3	Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism.

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)
ANGPTL3	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen-like_C

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
liver	1
nephron tubule	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANGPTL3	153	tissue_specific	marker	right lobe of liver, liver, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANGPTL3	1,279

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANGPTL3	Q9Y5C1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	1142.0×	0.005	ANGPTL3
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.005	ANGPTL3
Plasma lipoprotein remodeling	1	475.8×	0.005	ANGPTL3
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.005	ANGPTL3
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.007	ANGPTL3
Signaling by Nuclear Receptors	1	102.0×	0.013	ANGPTL3
Transport of small molecules	1	25.1×	0.045	ANGPTL3
Signal Transduction	1	10.2×	0.098	ANGPTL3

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
regulation of chylomicron remodeling	1	8426.0×	0.003	ANGPTL3
acylglycerol homeostasis	1	3370.4×	0.003	ANGPTL3
negative regulation of very-low-density lipoprotein particle remodeling	1	2808.7×	0.003	ANGPTL3
positive regulation of lipid catabolic process	1	1872.4×	0.003	ANGPTL3
phospholipid catabolic process	1	1203.7×	0.003	ANGPTL3
glycerol metabolic process	1	1123.5×	0.003	ANGPTL3
phospholipid homeostasis	1	991.3×	0.003	ANGPTL3
artery morphogenesis	1	674.1×	0.004	ANGPTL3
lipid storage	1	543.6×	0.004	ANGPTL3
triglyceride homeostasis	1	481.5×	0.005	ANGPTL3
response to hormone	1	432.1×	0.005	ANGPTL3
phospholipid metabolic process	1	343.9×	0.005	ANGPTL3
lipid homeostasis	1	337.0×	0.005	ANGPTL3
cholesterol metabolic process	1	195.9×	0.008	ANGPTL3
fatty acid metabolic process	1	193.7×	0.008	ANGPTL3
cell-matrix adhesion	1	163.6×	0.008	ANGPTL3
integrin-mediated signaling pathway	1	160.5×	0.008	ANGPTL3
cholesterol homeostasis	1	156.0×	0.008	ANGPTL3
positive regulation of angiogenesis	1	115.4×	0.010	ANGPTL3
angiogenesis	1	62.4×	0.017	ANGPTL3
positive regulation of cell migration	1	61.7×	0.017	ANGPTL3
signal transduction	1	16.1×	0.062	ANGPTL3

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
ANGPTL3	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	ANGPTL3

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)
ANGPTL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.