ANGPTL3 (Angiopoietin-related protein 3) variants and mutations
ANGPTL3 (also known as Angiopoietin-related protein 3) is a human protein-coding gene encoding an angiopoietin-related protein 3 protein. It restrains lipoprotein and endothelial lipases, thereby increasing circulating triglyceride and HDL-cholesterol levels. Loss-of-function variants produce familial combined hypolipidemia and are associated with lower atherosclerotic cardiovascular risk, making the pathway a therapeutic target. This analysis covers 872 ANGPTL3 variants and mutations. Of these, 82% have computational variant effect predictions. Disease context includes familial hypobetalipoproteinemia 2, Hypercholesterolemia, and familial hypercholesterolemia. Example ANGPTL3 variants include F2I, F2F, and T3A.
Variant analysis overview
- Gene: ANGPTL3
- Protein: Angiopoietin-related protein 3
- UniProt accession: Q9Y5C1
- Organism: Homo sapiens
- Variants analyzed: 872
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 532 unspecified-consequence records; 106 synonymous variants; 158 missense variants; 8 in-frame deletions; 42 frameshift variants; 15 stop-gained variants; 4 splice-region variants; 7 substitution
- Prediction scores: 714 variants have prediction scores (82% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: familial hypobetalipoproteinemia 2, Hypercholesterolemia, familial hypercholesterolemia, homozygous familial hypercholesterolemia, cardiovascular disorder, metabolic disease, hereditary disease, genetic developmental and epileptic encephalopathy, hyperlipidemia, Disorder of lipid metabolism, hypertriglyceridemia, metabolic dysfunction-associated steatotic liver disease.
Protein structure and variant hotspots
- Protein features: 1 domains; 4 post-translational modification sites.
- Structural context: 318 variants have structural context.
- PTM context: 3 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable ANGPTL3 variants
Examples include F2I, F2F, T3A, T3T, I4V, L6P, L6F, L7R. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- F2I (p.Phe2Ile), ExAC rs772988115, gnomAD rs772988115, REVEL 0.04, CADD 11.40
- F2F (p.Phe2Phe), gnomAD 1-62597572-C-T, CADD 7.70
- T3A (p.Thr3Ala), TOPMed rs1649443987, gnomAD rs1649443987, REVEL 0.04, CADD 14.90
- T3T (p.Thr3Thr), rs1394023534, gnomAD 1-62597575-A-T, CADD 0.66
- I4V (p.Ile4Val), ExAC rs760521061, gnomAD rs760521061, REVEL 0.03, CADD 8.36
- L6P (p.Leu6Pro), ExAC rs766251086, gnomAD rs766251086, REVEL 0.15, CADD 23.00
- L6F (p.Leu6Phe), gnomAD 1-62597582-C-T, REVEL 0.07, CADD 3.65
- L7R (p.Leu7Arg), gnomAD 1-62597586-T-G, REVEL 0.24, CADD 23.20
- L7L (p.Leu7Leu), gnomAD 1-62597587-T-C, CADD 3.54
- L8I (p.Leu8Ile), NCI-TCGA Cosmic COSV9922, Variant assessed as somatic; moderate impact.
- L8del (p.Leu8del), gnomAD 1-62597584-CCTT-C, CADD 15.70
- L8F (p.Leu8Phe), rs1316616797, gnomAD 1-62597585-CT-C, CADD 24.40
- L8S (p.Leu8Ser), gnomAD 1-62597586-T-TA, CADD 24.60
- I10T (p.Ile10Thr), gnomAD rs1447204425, REVEL 0.26, CADD 18.20
- I10I (p.Ile10Ile), gnomAD 1-62597596-T-C, CADD 4.10
- P12L (p.Pro12Leu), gnomAD rs1216052225, REVEL 0.10, CADD 18.10
- P12P (p.Pro12Pro), gnomAD 1-62597602-T-G, CADD 9.19
- L13P (p.Leu13Pro), Ensembl rs779312263
- V14I (p.Val14Ile), NCI-TCGA Cosmic COSV5201, Variant assessed as somatic; moderate impact.
- V14L (p.Val14Leu), rs776558413, ClinGen CA886497, ClinVar RCV004414988, ExAC rs776558413, REVEL 0.13, CADD 22.70, Uncertain significance, Inborn genetic diseases
- V14D (p.Val14Asp), gnomAD 1-62597607-T-A, REVEL 0.31, CADD 24.60
- V14A (p.Val14Ala), gnomAD 1-62597607-T-C, REVEL 0.07, CADD 18.20
- I15N (p.Ile15Asn), rs1468270765, gnomAD 1-62597608-T-TA, CADD 23.40
- I15I (p.Ile15Ile), rs982453920, gnomAD 1-62597611-T-C, CADD 8.72
- S16C (p.Ser16Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S16* (p.Ser16Ter), gnomAD 1-62597606-GTTATT, CADD 25.20
- S16P (p.Ser16Pro), gnomAD 1-62597612-T-C, REVEL 0.05, CADD 19.40
- S16S (p.Ser16Ser), rs1649450548, gnomAD 1-62597614-C-T, CADD 4.76
- S17* (p.Ser17Ter), rs267606655, ClinGen CA117429, ClinVar RCV000005684, Ensembl rs267606655, Pathogenic
- S17C (p.Ser17Cys), ExAC rs758931786, TOPMed rs758931786, gnomAD rs758931786, REVEL 0.17, CADD 23.00
- S17F (p.Ser17Phe), ExAC rs758931786, TOPMed rs758931786, gnomAD rs758931786, REVEL 0.19, CADD 23.20
- S17S (p.Ser17Ser), rs764827703, gnomAD 1-62597617-C-A, CADD 4.07
- R18K (p.Arg18Lys), TOPMed rs1013469622, gnomAD rs1013469622, REVEL 0.07, CADD 7.82
- I19T (p.Ile19Thr), gnomAD 1-62597622-T-C, REVEL 0.07, CADD 7.89
- D20Y (p.Asp20Tyr), Ensembl rs1557775786, REVEL 0.18, CADD 23.30
- D20E (p.Asp20Glu), gnomAD 1-62597626-T-G, REVEL 0.01, CADD 0.18
- Q21H (p.Gln21His), rs752195217, ExAC rs752195217, gnomAD rs752195217, ClinGen CA886500, REVEL 0.06, CADD 17.50, Uncertain significance, Inborn genetic diseases
- Q21K (p.Gln21Lys), gnomAD 1-62597627-C-A, REVEL 0.14, CADD 10.30
- Q21P (p.Gln21Pro), gnomAD 1-62597628-A-C, REVEL 0.05, CADD 13.30
- Q21R (p.Gln21Arg), gnomAD 1-62597628-A-G, REVEL 0.06, CADD 12.10
- D22E (p.Asp22Glu), gnomAD 1-62597632-C-G, REVEL 0.05, CADD 1.74
- N23H (p.Asn23His), Ensembl rs1649455233, REVEL 0.07, CADD 3.62
- N23R (p.Asn23Arg), rs779437563, gnomAD 1-62597633-A-AG, CADD 18.10
- N23S (p.Asn23Ser), gnomAD 1-62597634-A-G, REVEL 0.04, CADD 2.58
- N23N (p.Asn23Asn), rs763902658, gnomAD 1-62597635-T-C, CADD 3.30
- S24* (p.Ser24Ter), Ensembl rs1364780951, CADD 24.40, Uncertain significance
- S24L (p.Ser24Leu), rs1364780951, ClinGen CA340599806, ClinVar RCV001979305, ClinVar RCV004044543, REVEL 0.05, CADD 7.56, Uncertain significance, Inborn genetic diseases; not provided
- S24P (p.Ser24Pro), ExAC rs751955393, gnomAD rs751955393, REVEL 0.02, CADD 8.92
- S24F (p.Ser24Phe), gnomAD 1-62597634-A-AT, CADD 18.20
- S25P (p.Ser25Pro), rs746135169, ClinGen CA23748231, ClinVar RCV002653399, TOPMed rs746135169, REVEL 0.03, CADD 5.75, Uncertain significance, not provided
- S25* (p.Ser25Ter), gnomAD 1-62597640-C-G, CADD 34.00
- S25S (p.Ser25Ser), gnomAD 1-62597641-A-C, CADD 9.54
- F26L (p.Phe26Leu), ESP rs143189908, ExAC rs143189908, TOPMed rs143189908, gnomAD rs143189908, REVEL 0.04, CADD 9.14
- D27H (p.Asp27His), Ensembl rs1649459413, REVEL 0.21, CADD 25.10
- S28F (p.Ser28Phe), gnomAD rs1165491527, REVEL 0.09, CADD 23.30
- S28C (p.Ser28Cys), gnomAD 1-62597649-C-G, REVEL 0.14, CADD 23.20
- L29I (p.Leu29Ile), NCI-TCGA Cosmic COSV5202, Variant assessed as somatic; moderate impact.
- L29P (p.Leu29Pro), TOPMed rs1255758366, REVEL 0.05, CADD 13.00
- L29L (p.Leu29Leu), rs781736614, gnomAD 1-62597651-C-T, CADD 0.21
- S30A (p.Ser30Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S30Y (p.Ser30Tyr), Ensembl rs1649462024
- S30I (p.Ser30Ile), rs1557775870, gnomAD 1-62597651-C-CT, CADD 19.60
- S30P (p.Ser30Pro), gnomAD 1-62597654-T-C, REVEL 0.02, CADD 4.28
- P31S (p.Pro31Ser), gnomAD rs1393534741, REVEL 0.01, CADD 15.20
- P31A (p.Pro31Ala), gnomAD 1-62597657-C-G, REVEL 0.05, CADD 15.00
- E32K (p.Glu32Lys), ExAC rs746416387, TOPMed rs746416387, gnomAD rs746416387, REVEL 0.21, CADD 23.60
- E32Q (p.Glu32Gln), ExAC rs746416387, TOPMed rs746416387, gnomAD rs746416387, REVEL 0.10, CADD 22.90
- E32D (p.Glu32Asp), gnomAD 1-62597662-G-T, REVEL 0.11, CADD 17.70
- P33S (p.Pro33Ser), NCI-TCGA Cosmic COSV9922, Variant assessed as somatic; moderate impact.
- P33T (p.Pro33Thr), gnomAD 1-62597663-C-A, REVEL 0.03, CADD 13.90
- P33L (p.Pro33Leu), gnomAD 1-62597664-C-T, REVEL 0.17, CADD 23.00
- K34N (p.Lys34Asn), gnomAD 1-62597668-A-T, REVEL 0.20, CADD 23.00
- S35P (p.Ser35Pro), gnomAD 1-62597669-T-C, REVEL 0.07, CADD 18.50
- S35* (p.Ser35Ter), gnomAD 1-62597670-C-A, CADD 35.00
- S35S (p.Ser35Ser), gnomAD 1-62597671-A-G, CADD 12.10
- R36I (p.Arg36Ile), NCI-TCGA Cosmic COSV9922, Variant assessed as somatic; moderate impact.
- R36K (p.Arg36Lys), Ensembl rs2149525229, REVEL 0.33, CADD 24.50
- R36S (p.Arg36Ser), TOPMed rs1319925385, gnomAD rs1319925385, REVEL 0.46, CADD 25.90
- R36T (p.Arg36Thr), gnomAD 1-62597673-G-C, REVEL 0.42, CADD 24.50
- F37L (p.Phe37Leu), gnomAD rs1326631750, REVEL 0.47, CADD 27.10
- F37S (p.Phe37Ser), gnomAD 1-62597676-T-C, REVEL 0.59, CADD 28.30
- F37C (p.Phe37Cys), gnomAD 1-62597676-T-G, REVEL 0.58, CADD 27.80
- F37F (p.Phe37Phe), rs756096244, gnomAD 1-62597677-T-C, CADD 12.30
- A38D (p.Ala38Asp), TOPMed rs1267929323, gnomAD rs1267929323, REVEL 0.51, CADD 25.20
- A38P (p.Ala38Pro), TOPMed rs1649466334
- A38V (p.Ala38Val), TOPMed rs1267929323, gnomAD rs1267929323, REVEL 0.47, CADD 25.20
- M39I (p.Met39Ile), gnomAD rs1235689920, REVEL 0.20, CADD 24.10
- M39T (p.Met39Thr), TOPMed rs1336207471, gnomAD rs1336207471, REVEL 0.25, CADD 23.90
- M39V (p.Met39Val), gnomAD 1-62597681-A-G, REVEL 0.17, CADD 22.60
- L40S (p.Leu40Ser), TOPMed rs1462766918
- L40L (p.Leu40Leu), rs2149525287, gnomAD 1-62597684-T-C, CADD 9.16
- D41N (p.Asp41Asn), NCI-TCGA Cosmic COSV9922, Variant assessed as somatic; moderate impact.
- D41D (p.Asp41Asp), rs780153441, gnomAD 1-62597689-C-T, CADD 8.13
- D42N (p.Asp42Asn), ExAC rs199772471, TOPMed rs199772471, gnomAD rs199772471, REVEL 0.37, CADD 27.20
- D42D (p.Asp42Asp), rs147500008, gnomAD 1-62597692-T-C, CADD 8.34
- V43I (p.Val43Ile), gnomAD 1-62597693-G-A, REVEL 0.44, CADD 25.30
- V43A (p.Val43Ala), gnomAD 1-62597694-T-C, REVEL 0.54, CADD 25.90
- K44N (p.Lys44Asn), ExAC rs774569842, gnomAD rs774569842, REVEL 0.15, CADD 22.90
- K44Q (p.Lys44Gln), gnomAD 1-62597696-A-C, REVEL 0.09, CADD 23.10
- I45T (p.Ile45Thr), ExAC rs746743905, gnomAD rs746743905, REVEL 0.17, CADD 21.80
- I45V (p.Ile45Val), TOPMed rs1032082501, gnomAD rs1032082501, REVEL 0.15, CADD 19.00
- L46V (p.Leu46Val), gnomAD 1-62597702-T-G, REVEL 0.28, CADD 23.00
- A47G (p.Ala47Gly), gnomAD 1-62597706-C-G, REVEL 0.29, CADD 20.70
- A47A (p.Ala47Ala), rs1649471973, gnomAD 1-62597707-C-T, CADD 7.32
- N48S (p.Asn48Ser), ExAC rs770747783
- N48N (p.Asn48Asn), gnomAD 1-62597710-T-C, CADD 9.90
- L50F (p.Leu50Phe), Ensembl rs2149525350
- L50P (p.Leu50Pro), ESP rs151064896, ExAC rs151064896, TOPMed rs151064896, gnomAD rs151064896
- L50R (p.Leu50Arg), ESP rs151064896, ExAC rs151064896, TOPMed rs151064896, gnomAD rs151064896, REVEL 0.53, CADD 27.10
- L50L (p.Leu50Leu), gnomAD 1-62597716-C-G, CADD 7.67
- L51V (p.Leu51Val), ESP rs139687521, TOPMed rs139687521, REVEL 0.36, CADD 24.50
- L53W (p.Leu53Trp), ExAC rs765123937, gnomAD rs765123937, REVEL 0.63, CADD 26.80
- L53L (p.Leu53Leu), rs759491919, gnomAD 1-62597723-T-C, CADD 8.55
- L53V (p.Leu53Val), gnomAD 1-62597723-T-G, REVEL 0.35, CADD 23.10
- G54E (p.Gly54Glu), gnomAD 1-62597727-G-A, REVEL 0.67, CADD 26.40
- G54G (p.Gly54Gly), gnomAD 1-62597728-A-G, CADD 7.25
- H55N (p.His55Asn), gnomAD 1-62597729-C-A, REVEL 0.21, CADD 23.70
- H55R (p.His55Arg), gnomAD 1-62597730-A-G, REVEL 0.15, CADD 21.10
- H55H (p.His55His), rs775056868, gnomAD 1-62597731-T-C, CADD 5.97
- G56V (p.Gly56Val), TOPMed rs1320821302
- G56G (p.Gly56Gly), gnomAD 1-62597734-T-C, CADD 9.44
- L57H (p.Leu57His), NCI-TCGA Cosmic COSV5202, Variant assessed as somatic; moderate impact.
- L57L (p.Leu57Leu), rs533410817, gnomAD 1-62597737-T-C, CADD 7.96
- K58E (p.Lys58Glu), ExAC rs763781510, gnomAD rs763781510, REVEL 0.28, CADD 25.40
- K58N (p.Lys58Asn), ExAC rs751260529, gnomAD rs751260529
- K58R (p.Lys58Arg), gnomAD 1-62597739-A-G, REVEL 0.08, CADD 17.70
- K58K (p.Lys58Lys), gnomAD 1-62597740-A-G, CADD 10.70
- D59H (p.Asp59His), TOPMed rs1160109040, gnomAD rs1160109040, REVEL 0.41, CADD 27.00
- F60L (p.Phe60Leu), rs1385349486, gnomAD 1-62597742-AC-A, CADD 23.20
- F60C (p.Phe60Cys), gnomAD 1-62597743-CTT-C, CADD 26.90
- F60F (p.Phe60Phe), rs546051366, gnomAD 1-62597746-T-C, CADD 10.60
- V61D (p.Val61Asp), ExAC rs768014539, TOPMed rs768014539, gnomAD rs768014539
- V61V (p.Val61Val), rs370895328, gnomAD 1-62597749-C-T, CADD 7.83
- H62P (p.His62Pro), TOPMed rs1356877257, gnomAD rs1356877257, REVEL 0.32, CADD 25.20
- H62R (p.His62Arg), TOPMed rs1356877257, gnomAD rs1356877257, REVEL 0.23, CADD 23.30
- H62H (p.His62His), gnomAD 1-62597752-T-C, CADD 7.58
- K63E (p.Lys63Glu), TOPMed rs1649482350, gnomAD rs1649482350, REVEL 0.57, CADD 26.00
- K63M (p.Lys63Met), ESP rs146749211, ExAC rs146749211, TOPMed rs146749211, gnomAD rs146749211, REVEL 0.70, CADD 26.30
- K63T (p.Lys63Thr), rs146749211, UniProt VAR 075670, ESP rs146749211, ExAC rs146749211, REVEL 0.67, CADD 25.80, Benign
- T64A (p.Thr64Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- T64K (p.Thr64Lys), ExAC rs756641927, TOPMed rs756641927, gnomAD rs756641927, REVEL 0.47, CADD 24.10
- T64M (p.Thr64Met), rs756641927, ExAC rs756641927, TOPMed rs756641927, gnomAD rs756641927, REVEL 0.40, CADD 24.20, Variant assessed as somatic; moderate impact.
- T64R (p.Thr64Arg), ExAC rs756641927, TOPMed rs756641927, gnomAD rs756641927
- T64T (p.Thr64Thr), rs753899075, gnomAD 1-62597758-G-T, CADD 5.22
- K65* (p.Lys65Ter), gnomAD 1-62597759-A-T, CADD 36.00
- K65T (p.Lys65Thr), gnomAD 1-62597760-A-C, REVEL 0.47, CADD 25.40
- G66D (p.Gly66Asp), ExAC rs755058329, TOPMed rs755058329, gnomAD rs755058329, REVEL 0.31, CADD 24.70
- G66G (p.Gly66Gly), rs779071619, gnomAD 1-62597764-C-A, CADD 6.62
- Q67* (p.Gln67Ter), ExAC rs748393501, TOPMed rs748393501, gnomAD rs748393501
- Q67P (p.Gln67Pro), ExAC rs772332226, gnomAD rs772332226, REVEL 0.60, CADD 25.00
- I68V (p.Ile68Val), Ensembl rs1649487312
- N69S (p.Asn69Ser), gnomAD 1-62597772-A-G, REVEL 0.10, CADD 22.60
- N69N (p.Asn69Asn), rs369780744, gnomAD 1-62597773-T-C, CADD 7.41
- D70N (p.Asp70Asn), ExAC rs745714568, TOPMed rs745714568, gnomAD rs745714568, REVEL 0.34, CADD 27.20
- I71T (p.Ile71Thr), ExAC rs769753498, TOPMed rs769753498, gnomAD rs769753498, REVEL 0.46, CADD 25.70
- I71V (p.Ile71Val), gnomAD 1-62597777-A-G, REVEL 0.34, CADD 24.60
- F72L (p.Phe72Leu), ExAC rs775299081, TOPMed rs775299081, gnomAD rs775299081, REVEL 0.13, CADD 22.80
- F72F (p.Phe72Phe), rs775299081, gnomAD 1-62597782-T-C, CADD 11.60
- Q73K (p.Gln73Lys), rs145578974, ClinGen CA886537, ClinVar RCV002692437, ESP rs145578974, REVEL 0.12, CADD 16.40, Uncertain significance, Inborn genetic diseases
- K74N (p.Lys74Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- L75F (p.Leu75Phe), ExAC rs768313034, TOPMed rs768313034, gnomAD rs768313034, REVEL 0.43, CADD 24.70
- L75T (p.Leu75Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- N76K (p.Asn76Lys), rs149086653, ClinGen CA886539, ClinVar RCV001516306, ClinVar RCV001516307, REVEL 0.12, CADD 21.90, Benign/Likely benign, Developmental and epileptic encephalopathy, 23; not provided
- N76Y (p.Asn76Tyr), gnomAD 1-62597792-A-T, REVEL 0.07, CADD 20.50
- N76N (p.Asn76Asn), rs149086653, gnomAD 1-62597794-C-T, CADD 8.05
- I77M (p.Ile77Met), gnomAD rs1156523401, REVEL 0.23, CADD 23.30
- F78L (p.Phe78Leu), gnomAD 1-62597798-T-C, REVEL 0.36, CADD 26.70
- D79N (p.Asp79Asn), ExAC rs767345973, TOPMed rs767345973, gnomAD rs767345973, REVEL 0.25, CADD 24.70
- D79V (p.Asp79Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D79Y (p.Asp79Tyr), ExAC rs767345973, TOPMed rs767345973, gnomAD rs767345973, REVEL 0.58, CADD 26.90
- D79I (p.Asp79Ile), rs1207982736, gnomAD 1-62597800-TG-T, CADD 29.50
- Q80E (p.Gln80Glu), TOPMed rs201052110, gnomAD rs201052110, REVEL 0.14, CADD 19.90
- Q80* (p.Gln80Ter), gnomAD 1-62597804-C-T, CADD 35.00
- Q80R (p.Gln80Arg), gnomAD 1-62597805-A-G, REVEL 0.07, CADD 16.10
- Q80H (p.Gln80His), gnomAD 1-62597806-G-C, REVEL 0.05, CADD 19.40
- S81Y (p.Ser81Tyr), gnomAD 1-62597808-C-A, REVEL 0.38, CADD 23.70
- S81S (p.Ser81Ser), rs141150415, gnomAD 1-62597809-T-C, CADD 10.40
- F82C (p.Phe82Cys), gnomAD rs1373030963, REVEL 0.32, CADD 27.00
- Y83* (p.Tyr83Ter), TOPMed rs920003542, gnomAD rs920003542, CADD 35.00
- Y83H (p.Tyr83His), gnomAD rs1649497318, REVEL 0.30, CADD 23.20
Public ANGPTL3 analysis runs
- ANGPTL3 analysis run — ANGPTL3 (872 variants) — completed 2026-08-19