APOE (Apolipoprotein E) variants and mutations
APOE (also known as Apolipoprotein E) is a human protein-coding gene encoding an apolipoprotein E protein. It redistributes cholesterol and other lipids between tissues by directing remnant lipoproteins to LDL-receptor-family members. The common epsilon4 isoform strongly increases late-onset Alzheimer disease risk and also influences plasma lipids and cardiovascular risk. This analysis covers 678 APOE variants and mutations. Of these, 90% have computational variant effect predictions. Disease context includes hyperlipoproteinemia type 3, coronary artery disorder, and lipoprotein glomerulopathy. Example APOE variants include K2E, K2Q, and K2K.
Variant analysis overview
- Gene: APOE
- Protein: Apolipoprotein E
- UniProt accession: P02649
- Organism: Homo sapiens
- Variants analyzed: 678
- Variant scope: all variants
- Completed: 2026-08-10
Variant and mutation evidence
- Variant composition: 512 unspecified-consequence records; 83 missense variants; 6 stop-gained variants; 17 frameshift variants; 49 synonymous variants; 3 splice-region variants; 2 in-frame deletions; 6 substitution
- Prediction scores: 612 variants have prediction scores (90% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hyperlipoproteinemia type 3, coronary artery disorder, lipoprotein glomerulopathy, Alzheimer disease, familial hypercholesterolemia, dementia, late-onset Alzheimers disease, Hypercholesterolemia, metabolic syndrome, Sea-blue histiocytosis, diabetes mellitus, hypertensive disorder.
Protein structure and variant hotspots
- Protein features: 2 binding sites; 9 post-translational modification sites.
- PTM context: 15 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, MaveDB, LitVar.
Notable APOE variants
Examples include K2E, K2Q, K2K, K2R, V3F, L4L, W5*, W5G. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- K2E (p.Lys2Glu), gnomAD 19-44905890-A-G, CADD 1.99
- K2Q (p.Lys2Gln), gnomAD 19-44905890-A-C, CADD 1.75
- K2K (p.Lys2Lys), gnomAD 19-44905892-G-A, CADD 7.45
- K2R (p.Lys2Arg), gnomAD 19-44906627-GA-G, CADD 32.00
- V3F (p.Val3Phe), gnomAD 19-44906631-G-T, REVEL 0.49, CADD 22.50
- L4L (p.Leu4Leu), rs1270059098, gnomAD 19-44906634-C-T, CADD 14.30
- W5* (p.Trp5Ter), ExAC rs777551553, TOPMed rs777551553, gnomAD rs777551553, CADD 36.00
- W5G (p.Trp5Gly), gnomAD 19-44905896-T-G, CADD 6.38
- W5C (p.Trp5Cys), gnomAD 19-44905898-G-T, CADD 0.83
- W5L (p.Trp5Leu), gnomAD 19-44905915-G-T, CADD 7.71
- W5R (p.Trp5Arg), gnomAD 19-44906637-T-C, REVEL 0.66, CADD 26.90
- A6T (p.Ala6Thr), Ensembl rs1568615382, REVEL 0.47, CADD 22.80
- A6P (p.Ala6Pro), gnomAD 19-44905877-AG-A, CADD 8.32
- A6S (p.Ala6Ser), rs1434244093, gnomAD 19-44905881-G-T, CADD 1.92
- A6V (p.Ala6Val), gnomAD 19-44905882-C-T, CADD 6.43
- A6D (p.Ala6Asp), rs1969797567, gnomAD 19-44905882-C-A, CADD 5.80
- A6A (p.Ala6Ala), rs1174330636, gnomAD 19-44905883-C-A, CADD 5.89
- A7P (p.Ala7Pro), rs1969812567, ClinGen CA406301995, ClinVar RCV004417832, TOPMed rs1969812567, REVEL 0.48, CADD 18.10, Uncertain significance, Cardiovascular phenotype
- A7T (p.Ala7Thr), TOPMed rs1969812567, Uncertain significance
- A7V (p.Ala7Val), ExAC rs754318486, TOPMed rs754318486, gnomAD rs754318486, REVEL 0.18, CADD 5.39
- A7G (p.Ala7Gly), rs778989940, gnomAD 19-44906636-G-GTG, CADD 27.10
- A7A (p.Ala7Ala), gnomAD 19-44906645-G-A, CADD 6.46
- L8* (p.Leu8Ter), TOPMed rs923895447
- L8L (p.Leu8Leu), rs978402858, gnomAD 19-44906646-T-C, CADD 1.81
- L8F (p.Leu8Phe), gnomAD 19-44906648-G-T, REVEL 0.40, CADD 23.40
- L9P (p.Leu9Pro), ExAC rs779278130, gnomAD rs779278130, REVEL 0.61, CADD 23.80
- L9L (p.Leu9Leu), gnomAD 19-44906649-C-T, CADD 5.25
- V10G (p.Val10Gly), Ensembl rs1599950832
- V10I (p.Val10Ile), gnomAD rs1461741495, REVEL 0.32, CADD 14.30
- T11A (p.Thr11Ala), rs144354013, ClinGen CA9505931, ClinVar RCV002468440, ClinVar RCV005692483, REVEL 0.25, CADD 0.29, Conflicting interpretations, Lipoprotein glomerulopathy; Familial type 3 hyperlipoproteinemia; Cardiovascular
- T11S (p.Thr11Ser), 1000Genomes rs144354013, ExAC rs144354013, TOPMed rs144354013, gnomAD rs144354013, REVEL 0.19, CADD 0.25, Uncertain significance, Alzheimer disease 2
- T11P (p.Thr11Pro), gnomAD 19-44906655-A-C, REVEL 0.51, CADD 7.75
- T11I (p.Thr11Ile), gnomAD 19-44906656-C-T, REVEL 0.29, CADD 19.40
- F12L (p.Phe12Leu), TOPMed rs1381224336, gnomAD rs1381224336, REVEL 0.28, CADD 15.80
- F12Y (p.Phe12Tyr), ExAC rs747078681, TOPMed rs747078681, gnomAD rs747078681, REVEL 0.29, CADD 23.80
- F12F (p.Phe12Phe), rs1381224336, gnomAD 19-44906660-C-T, CADD 13.20
- L13R (p.Leu13Arg), Ensembl rs1568615443, REVEL 0.77, CADD 29.20
- L13L (p.Leu13Leu), gnomAD 19-44906661-C-T, CADD 13.70
- A14T (p.Ala14Thr), 1000Genomes rs559532612, TOPMed rs559532612, REVEL 0.16, CADD 22.00
- A14A (p.Ala14Ala), rs768934589, gnomAD 19-44906666-A-G, CADD 23.90
- G15* (p.Gly15Ter), Ensembl rs752693941, CADD 58.00
- G15V (p.Gly15Val), gnomAD 19-44905879-G-T, CADD 10.80
- G15E (p.Gly15Glu), rs373985746, gnomAD 19-44905879-G-A, CADD 11.50
- G15G (p.Gly15Gly), rs749645156, gnomAD 19-44905880-G-A, CADD 10.00
- G15R (p.Gly15Arg), rs1969798360, gnomAD 19-44905905-G-A, CADD 0.18
- G15A (p.Gly15Ala), gnomAD 19-44905906-G-C, CADD 2.28
- G15D (p.Gly15Asp), rs1214824838, gnomAD 19-44906617-G-A, CADD 10.70
- C16C (p.Cys16Cys), gnomAD 19-44907764-C-T, CADD 12.40
- A18D (p.Ala18Asp), NCI-TCGA Cosmic COSV9937, Variant assessed as somatic; moderate impact.
- A18P (p.Ala18Pro), 1000Genomes rs533904656, ExAC rs533904656, TOPMed rs533904656, gnomAD rs533904656, REVEL 0.62, CADD 24.90
- A18T (p.Ala18Thr), 1000Genomes rs533904656, ExAC rs533904656, TOPMed rs533904656, gnomAD rs533904656, REVEL 0.52, CADD 23.20, Likely benign, Cardiovascular phenotype
- A18S (p.Ala18Ser), gnomAD 19-44907768-G-T, REVEL 0.55, CADD 22.90
- K19R (p.Lys19Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K19E (p.Lys19Glu), gnomAD 19-44906622-A-G, CADD 22.70
- K19T (p.Lys19Thr), gnomAD 19-44906623-A-C, CADD 20.10
- V20L (p.Val20Leu), gnomAD 19-44907774-G-T, REVEL 0.35, CADD 2.91
- V20A (p.Val20Ala), gnomAD 19-44907775-T-C, REVEL 0.40, CADD 9.35
- V20V (p.Val20Val), rs1432394655, gnomAD 19-44907776-G-A, CADD 6.54
- E21K (p.Glu21Lys), rs121918392, ClinGen CA127499, ClinVar RCV000019429, UniProt VAR 000645, REVEL 0.56, CADD 20.20, Pathogenic, HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5
- E21* (p.Glu21Ter), gnomAD 19-44907777-G-T, CADD 34.00
- E21E (p.Glu21Glu), rs763720372, gnomAD 19-44907779-G-A, CADD 5.96
- E21D (p.Glu21Asp), gnomAD 19-44907779-G-T, REVEL 0.15, CADD 13.90
- Q22* (p.Gln22Ter), TOPMed rs1969834382
- Q22H (p.Gln22His), TOPMed rs1456562720, gnomAD rs1456562720, REVEL 0.26, CADD 8.76
- A23V (p.Ala23Val), ExAC rs776242156, TOPMed rs776242156, gnomAD rs776242156, REVEL 0.34, CADD 0.05
- A23T (p.Ala23Thr), gnomAD 19-44907783-G-A, REVEL 0.26, CADD 2.03
- A23G (p.Ala23Gly), gnomAD 19-44907784-C-G, REVEL 0.24, CADD 0.07
- A23E (p.Ala23Glu), gnomAD 19-44907784-C-A, REVEL 0.45, CADD 0.00
- A23A (p.Ala23Ala), rs111833428, gnomAD 19-44907785-G-A, CADD 5.20
- V24G (p.Val24Gly), TOPMed rs1969834815
- V24L (p.Val24Leu), TOPMed rs1394832846, gnomAD rs1394832846, REVEL 0.30, CADD 0.52, Uncertain significance, not provided
- V24M (p.Val24Met), TOPMed rs1394832846, gnomAD rs1394832846, REVEL 0.25, CADD 2.61
- E25K (p.Glu25Lys), Ensembl rs1440976751
- E25* (p.Glu25Ter), gnomAD 19-44907789-G-T, CADD 28.10
- E25D (p.Glu25Asp), gnomAD 19-44907791-G-C, REVEL 0.13, CADD 5.74
- T26A (p.Thr26Ala), Ensembl rs1969835105, REVEL 0.16, CADD 0.26, Likely benign, Cardiovascular phenotype
- T26K (p.Thr26Lys), rs1468448662, gnomAD 19-44906614-C-A, CADD 16.50
- E27A (p.Glu27Ala), gnomAD 19-44907793-CAG-C, CADD 21.20
- P28L (p.Pro28Leu), ExAC rs764929617, TOPMed rs764929617, gnomAD rs764929617, REVEL 0.20, CADD 0.22
- P28S (p.Pro28Ser), gnomAD rs1969835176, REVEL 0.17, CADD 0.09
- P28T (p.Pro28Thr), gnomAD 19-44905902-C-A, CADD 7.76
- P28R (p.Pro28Arg), gnomAD 19-44905903-C-G, CADD 0.29
- P28H (p.Pro28His), gnomAD 19-44905903-C-A, CADD 0.27
- P28P (p.Pro28Pro), gnomAD 19-44905904-T-A, CADD 0.58
- E29G (p.Glu29Gly), gnomAD 19-44907802-A-G, REVEL 0.31, CADD 14.70
- E29E (p.Glu29Glu), gnomAD 19-44907803-G-A, CADD 0.93
- E29D (p.Glu29Asp), gnomAD 19-44907803-G-C, REVEL 0.17, CADD 0.55
- P30T (p.Pro30Thr), gnomAD 19-44907804-C-A, REVEL 0.12, CADD 0.24
- P30P (p.Pro30Pro), gnomAD 19-44907806-C-A, CADD 0.18
- E31K (p.Glu31Lys), rs201672011, ClinGen CA041327, ClinVar RCV000019443, ClinVar RCV000019453, REVEL 0.42, CADD 15.90, Pathogenic, Familial type 3 hyperlipoproteinemia
- L32L (p.Leu32Leu), gnomAD 19-44907810-C-T, CADD 0.37
- R33C (p.Arg33Cys), ExAC rs752079771, TOPMed rs752079771, gnomAD rs752079771, REVEL 0.28, CADD 13.50
- R33H (p.Arg33His), TOPMed rs1212454788, gnomAD rs1212454788, REVEL 0.31, CADD 0.10, Likely benign, Cardiovascular phenotype
- R33L (p.Arg33Leu), NCI-TCGA TCGA novel, REVEL 0.35, CADD 0.05, Variant assessed as somatic; moderate impact.
- R33G (p.Arg33Gly), gnomAD 19-44905887-A-G, CADD 9.38
- R33R (p.Arg33Arg), gnomAD 19-44905887-A-C, CADD 9.09
- R33K (p.Arg33Lys), rs1246551383, gnomAD 19-44905888-G-A, CADD 4.90
- R33T (p.Arg33Thr), gnomAD 19-44905888-G-C, CADD 4.48
- R33S (p.Arg33Ser), gnomAD 19-44905889-A-T, CADD 5.35
- Q34* (p.Gln34Ter), Ensembl rs1969835794, CADD 27.00
- Q34H (p.Gln34His), Ensembl rs2122132426, REVEL 0.29, CADD 0.14
- Q34P (p.Gln34Pro), gnomAD 19-44907817-A-C, REVEL 0.29, CADD 3.68
- Q35L (p.Gln35Leu), gnomAD rs1249808975
- Q35R (p.Gln35Arg), gnomAD rs1249808975, REVEL 0.39, CADD 0.00
- Q35P (p.Gln35Pro), gnomAD 19-44907820-A-C, REVEL 0.54, CADD 0.01
- Q35Q (p.Gln35Gln), gnomAD 19-44907821-G-A, CADD 2.55
- Q35H (p.Gln35His), gnomAD 19-44907821-G-T, REVEL 0.36, CADD 7.76
- T36A (p.Thr36Ala), Ensembl rs2122132454, REVEL 0.21, CADD 0.15
- T36S (p.Thr36Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- T36T (p.Thr36Thr), rs755434388, gnomAD 19-44907824-C-G, CADD 0.37
- E37K (p.Glu37Lys), rs142480126, NCI-TCGA Cosmic COSV9937, ESP rs142480126, ExAC rs142480126, REVEL 0.21, CADD 0.06, Uncertain significance, Alzheimer disease 2
- W38* (p.Trp38Ter), rs2122132512, ClinGen CA406303231, ClinVar RCV001776850, Ensembl rs2122132512, Uncertain significance
- W38L (p.Trp38Leu), TOPMed rs1301411037, gnomAD rs1301411037, REVEL 0.19, CADD 20.00
- Q39R (p.Gln39Arg), rs756353413, ClinGen CA9505979, ClinVar RCV004417831, ExAC rs756353413, REVEL 0.23, CADD 17.90, Uncertain significance, Cardiovascular phenotype
- Q39* (p.Gln39Ter), gnomAD 19-44907831-C-T, CADD 33.00
- S40C (p.Ser40Cys), gnomAD 19-44905872-A-T, CADD 8.13
- S40N (p.Ser40Asn), gnomAD 19-44905873-G-A, CADD 1.22
- S40I (p.Ser40Ile), rs1470816009, gnomAD 19-44905873-G-T, CADD 0.97
- S40R (p.Ser40Arg), gnomAD 19-44905874-C-A, CADD 4.81
- S40P (p.Ser40Pro), gnomAD 19-44905875-T-C, CADD 6.96
- S40* (p.Ser40Ter), gnomAD 19-44905876-C-A, CADD 2.60
- S40S (p.Ser40Ser), rs1969797319, gnomAD 19-44905877-A-G, CADD 6.03
- S40L (p.Ser40Leu), rs1969797617, gnomAD 19-44905881-GC-G, CADD 4.40
- S40Y (p.Ser40Tyr), gnomAD 19-44905885-C-A, CADD 7.30
- S40F (p.Ser40Phe), rs1377502673, gnomAD 19-44905885-C-T, CADD 7.88
- S40G (p.Ser40Gly), gnomAD 19-44905893-A-G, CADD 9.34
- S40T (p.Ser40Thr), rs1233347077, gnomAD 19-44905894-G-C, CADD 6.80
- G41D (p.Gly41Asp), Ensembl rs1599951908
- G41S (p.Gly41Ser), rs749406635, ExAC rs749406635, TOPMed rs749406635, gnomAD rs749406635, REVEL 0.20, CADD 1.81, Variant assessed as somatic; moderate impact.
- G41V (p.Gly41Val), gnomAD 19-44907838-G-T, REVEL 0.37, CADD 14.50
- Q42* (p.Gln42Ter), NCI-TCGA Cosmic COSV5298, CADD 35.00, Variant assessed as somatic; high impact.
- Q42K (p.Gln42Lys), Ensembl rs1969836611
- Q42P (p.Gln42Pro), rs2513539611, ClinGen CA406303288, ClinVar RCV002430161, Uncertain significance, Cardiovascular phenotype
- Q42Q (p.Gln42Gln), rs1599951917, gnomAD 19-44907842-G-A, CADD 7.83
- R43C (p.Arg43Cys), rs121918399, ClinGen CA127525, ClinVar RCV000019468, ClinVar RCV002496418, REVEL 0.60, CADD 23.30, Pathogenic/Likely pathogenic, Cardiovascular phenotype; Lipoprotein glomerulopathy; Age related macular degene
- R43H (p.Arg43His), ESP rs371694216, ExAC rs371694216, TOPMed rs371694216, gnomAD rs371694216, REVEL 0.34, CADD 22.30
- R43L (p.Arg43Leu), NCI-TCGA Cosmic COSV5298, ESP rs371694216, ExAC rs371694216, TOPMed rs371694216, Variant assessed as somatic; moderate impact., in LPG
- R43P (p.Arg43Pro), ESP rs371694216, ExAC rs371694216, TOPMed rs371694216, gnomAD rs371694216
- p.Arg43 Ala47del, rs768374191, gnomAD 19-44907842-GCGCT, CADD 17.90
- W44* (p.Trp44Ter), ExAC rs768684471, gnomAD rs768684471, CADD 36.00
- W44R (p.Trp44Arg), gnomAD 19-44907846-T-C, REVEL 0.76, CADD 25.90
- E45G (p.Glu45Gly), Ensembl rs1599951966
- L46P (p.Leu46Pro), rs769452, ClinGen CA041808, ClinVar RCV000019456, ClinVar RCV000429606, REVEL 0.53, CADD 0.72, Pathogenic/Likely pathogenic, Familial hypercholesterolemia; APOE4(-)-FREIBURG
- L46Q (p.Leu46Gln), 1000Genomes rs769452, ESP rs769452, ExAC rs769452, TOPMed rs769452, Pathogenic
- L46L (p.Leu46Leu), rs761381769, gnomAD 19-44907854-G-A, CADD 5.91
- A47H (p.Ala47His), gnomAD 19-44907853-TG-T, CADD 22.30
- A47V (p.Ala47Val), gnomAD 19-44907856-C-T, REVEL 0.47, CADD 18.60
- A47A (p.Ala47Ala), rs1599952000, gnomAD 19-44907857-A-G, CADD 0.63
- L48R (p.Leu48Arg), NCI-TCGA Cosmic COSV9937, Variant assessed as somatic; moderate impact.
- L48V (p.Leu48Val), gnomAD rs1439276876, REVEL 0.17, CADD 2.32
- L48L (p.Leu48Leu), gnomAD 19-44907858-C-T, CADD 3.77
- G49D (p.Gly49Asp), Ensembl rs1599952025, REVEL 0.45, CADD 13.40
- G49S (p.Gly49Ser), Ensembl rs1599952017
- R50C (p.Arg50Cys), ExAC rs11542029, TOPMed rs11542029, gnomAD rs11542029, REVEL 0.56, CADD 25.90, Uncertain significance
- R50G (p.Arg50Gly), ExAC rs11542029, TOPMed rs11542029, gnomAD rs11542029, REVEL 0.53, CADD 24.70, Uncertain significance
- R50H (p.Arg50His), rs762461580, NCI-TCGA Cosmic COSV9937, ExAC rs762461580, REVEL 0.47, CADD 23.90, Variant assessed as somatic; moderate impact.
- R50L (p.Arg50Leu), ExAC rs762461580, TOPMed rs762461580, gnomAD rs762461580, REVEL 0.54, CADD 23.90
- R50P (p.Arg50Pro), ExAC rs762461580, TOPMed rs762461580, gnomAD rs762461580, REVEL 0.65, CADD 24.10
- R50S (p.Arg50Ser), rs11542029, ClinGen CA406303398, ClinVar RCV000520712, ExAC rs11542029, REVEL 0.50, CADD 24.70, Uncertain significance, not provided
- R50R (p.Arg50Arg), rs11542031, gnomAD 19-44907866-C-T, CADD 9.70
- F51V (p.Phe51Val), gnomAD 19-44907867-T-G, REVEL 0.52, CADD 23.20
- F51I (p.Phe51Ile), gnomAD 19-44907867-T-A, REVEL 0.57, CADD 23.20
- F51F (p.Phe51Phe), rs1599952085, gnomAD 19-44907869-T-C, CADD 11.50
- W52L (p.Trp52Leu), gnomAD 19-44907871-G-T, REVEL 0.56, CADD 25.20
- D53V (p.Asp53Val), Ensembl rs1969838529, REVEL 0.65, CADD 25.40
- D53T (p.Asp53Thr), gnomAD 19-44905896-TG-T, CADD 7.30
- D53A (p.Asp53Ala), gnomAD 19-44905900-A-C, CADD 10.40
- D53E (p.Asp53Glu), gnomAD 19-44905901-C-A, CADD 10.90
- D53D (p.Asp53Asp), gnomAD 19-44905901-C-T, CADD 11.60
- D53N (p.Asp53Asn), rs563571689, gnomAD 19-44905923-G-A, CADD 8.81
- Y54H (p.Tyr54His), gnomAD 19-44907876-T-C, REVEL 0.86, CADD 26.10
- L55Q (p.Leu55Gln), gnomAD 19-44907880-T-A, REVEL 0.81, CADD 25.70
- L55L (p.Leu55Leu), rs376607258, gnomAD 19-44907881-G-C, CADD 7.14
- R56C (p.Arg56Cys), NCI-TCGA Cosmic COSV5298, TOPMed rs1969838696, REVEL 0.60, CADD 26.10, Variant assessed as somatic; moderate impact.
- R56H (p.Arg56His), rs752790054, ClinGen CA9505994, NCI-TCGA Cosmic COSV9937, ClinVar RCV001776313, REVEL 0.31, CADD 23.00, Uncertain significance, Cardiovascular phenotype; not provided
- R56P (p.Arg56Pro), ExAC rs752790054, TOPMed rs752790054, gnomAD rs752790054, Uncertain significance
- R56S (p.Arg56Ser), gnomAD 19-44907882-C-A, REVEL 0.42, CADD 21.30
- Q59H (p.Gln59His), gnomAD 19-44907891-CAG-C, CADD 28.30
- Q59R (p.Gln59Arg), gnomAD 19-44907892-A-G, REVEL 0.56, CADD 25.20
- T60A (p.Thr60Ala), rs28931576, ClinGen CA127515, ClinVar RCV000019457, ClinVar RCV005384642, REVEL 0.18, CADD 15.50, Conflicting interpretations, Cardiovascular phenotype; Familial hypercholesterolemia
Public APOE analysis runs
- APOE analysis run — APOE (678 variants) — completed 2026-08-10