ANGPTL3

Chr 1

angiopoietin like 3

Also known as: ANG-5, ANGPT5, ANL3, FHBL2

NCBI Gene: 27329 ENSG00000132855 UniProt: Q9Y5C1

The encoded protein is a hepatokine that regulates lipid and glucose metabolism by inhibiting lipoprotein lipase activity and endothelial lipase, thereby affecting plasma triglyceride clearance and HDL cholesterol levels. Biallelic mutations cause familial hypobetalipoproteinemia type 2, inherited in an autosomal recessive pattern. This gene shows very low constraint against loss-of-function variants in the general population.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2. [provided by RefSeq, Aug 2015]

GeneReviews ResearchGenerating clinical summary…

DNmechanismLOEUF 1.30

Clinical Summary— ANGPTL3

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Gene-Disease Validity (ClinGen)

familial hypobetalipoproteinemia 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 70 VUS of 160 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ANGPTL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.30LOEUF

pLI 0.000

Z-score 0.43

OE 0.90 (0.64–1.30)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.09Z-score

OE missense 1.02 (0.91–1.13)

232 obs / 228.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.90 (0.64–1.30)

0≤0.351.4

Missense OE?1.02 (0.91–1.13)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 21 / 23.2Missense obs/exp: 232 / 228.0Syn Z: -0.63

This gene — mechanism propensity

0.6939th %ile

GOF

0.5955th %ile

LOF

0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic5

VUS70

Likely Benign59

Benign9

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	1	2	0	13
Likely Pathogenic	5	0	0	0	5
VUS	2	66	2	0	70
Likely Benign	1	4	20	34	59
Benign	0	1	6	2	9
Conflicting	—				3
Total	18	72	30	36	159

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap ANGPTL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ANGPTL3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — ANGPTL3

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Homozygous Familial Hypercholesterolemia (HoFH)Coronary Computed Tomography Angiography

Assessing the Impact of Intensification of Lipid Lowering Therapy With Guidelines-based Evinacumab Administration on Coronary Plaque Volumes Measured by Coronary Computed Tomography Angiography (CCTA) in Patients With Homozygous Familial Hypercholesterolemia (HoFH)

RECRUITING

NCT07447648Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)Started 2026-04-30

Pancreatic Ductal AdenocarcinomaPancreatic CancerPancreas Cancer

Cholesterol Disruption in Combination With the Standard of Care in Patients With Advanced Pancreatic Adenocarcinoma

ACTIVE NOT RECRUITING

NCT04862260Phase EARLY_PHASE1CHU de Quebec-Universite LavalStarted 2021-10-04

Cholesterol metabolism disruption

HypercholesterolemiaHypertriglyceridemiaRefractory Hyperlipidemia

Phase 1b Study of VERVE-201 in Patients With Refractory Hyperlipidemia

RECRUITING

NCT06451770Phase PHASE1Verve Therapeutics, Inc.Started 2024-10-30

VERVE-201