ANGPTL3

Chr 1AR

angiopoietin like 3

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

NCBI Gene: 27329 ENSG00000132855 UniProt: Q9Y5C1 OMIM: 604774

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hypobetalipoproteinemia, familial, 2MIM #605019

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · familial hypobetalipoproteinemia 2 · AR · ClinGen 2022

Active trials

234

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.30

LOEUF

Mechanism· predicted

📖

GeneReview available — ANGPTL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in ANGPTL3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

554 rare PASS variants

Rare truncating (LoF)

1 in 480

128 rare PASS variants

Rare synonymous (reference)

1 in 290

196 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ANGPTL3; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 490
South Asian	~43k	1 in 88	1 in 830
Remaining (unassigned)	~30k	1 in 110	1 in 440
European (Finnish)	~27k	1 in 280	1 in 3,700
Admixed American	~22k	1 in 110	1 in 770
African / African American	~21k	1 in 81	1 in 540
East Asian	~20k	1 in 95	1 in 990
Ashkenazi Jewish	~13k	1 in 450	≈ 1 in 6,500
Middle Eastern	~2,883	1 in 80	1 in 360

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓