Mutations

APOE

APOE encodes a secreted apolipoprotein involved in lipid metabolism. It is best known for its three major alleles—APOE2, APOE3, and APOE4 —with APOE4 increasing the risk for Alzheimer’s disease and APOE2 reducing it. Every person has an APOE genotype determined by pairs of these alleles: APOE3/E3 (the most common), APOE3/E4, APOE3/E2, APOE2/E4, APOE4/E4, or APOE2/E2. Other variants , many of them rare, have also been studied. Some have been tied to AD,  to other neurological disorders, and/or to peripheral conditions, including alterations of lipid metabolism, cardiovascular or kidney disease.

This dataset uses the sequence of the most common APOE allele, APOE3, as a reference. Departures from this sequence are listed as variants. Amino acid position is based on the full-length ApoE protein, 317 amino acids long, including the signal peptide. Positions based on the mature protein, 299 amino acids long, appear in gray (diagram) and in parentheses (table). References for ApoE domains and regions can be found in Methods.

Click on the amino acids in the diagram or on the “Additional Variants” box in the lower-right-hand corner. You can also click on the variants in the table below. See Dec 2022 news for more information.

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Search Results

APOE (154)

To request a download of the data in this table, please email mutations@alzforum.org

Mutation Clinical
Phenotype Studied
DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Biological Effect Primary
Papers
APOE Region
Alzheimer's Disease, Multiple Conditions Both

Multiple effects.

c.-1334G>A
(rs7259620)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Non-Coding 2kb upstream

Unknown, but predicted benign in silico (PHRED-scaled CADD =0.15).

Takei et al., 2009
c.-779_-776del
(rs538385866)
Alzheimer's Disease Deletion Non-Coding 2kb upstream

Unknown, but located in predicted promoter region.

Yee et al., 2021
c.-647A>G
(rs439382)
Alzheimer's Disease Substitution Non-Coding 2kb upstream

Unknown, but predicted benign in silico (PHRED-scaled CADD =0.45).

Reitz et al., 2013
g.45408560_45410359del
(DEL 19:44905303-44907102)
Alzheimer's Disease Deletion Deletion | Deletion Both Promoter, Exon 1, Exon 2

Predicted to eliminate APOE expression.

Chemparathy et al., 2024
c.-558A>T
(rs449647, -491A/T)
Alzheimer's Disease, Multiple Conditions Substitution Non-Coding 2kb upstream

Unclear, but several studies reported effects on APOE transcription.

Bullido et al., 1998
c.-494T>C
(rs769446, -427 T/C, -427C/T)
Alzheimer's Disease, Multiple Conditions Substitution Non-Coding 2kb upstream

Unclear, but some studies reported effects on APOE transcription.

Artiga et al., 1998;
Artiga et al., 1998
c.-488C>A
(rs532314089)
Alzheimer's Disease Substitution Non-Coding 2kb upstream

Unknown, but predicted to disrupt binding of transcription factor EGR1. PHRED-scaled CADD = 0.26.

Yee et al., 2021
c.-380A>G
(rs1038445539)
Hyperlipoproteinemia Type IIb Substitution Non-Coding 2kb upstream

Unknown, but predicted benign in silico (PHRED-scaled CADD = 7).

Abou Khalil et al., 2022
c.-286T>G
(rs405509, -219T/G, -219G/T, Th1/E47cs)
Alzheimer's Disease, Multiple Conditions Substitution Non-Coding 2kb upstream

Modified APOE transcription.

Artiga et al., 1998;
Lambert et al., 1998
c.-279G>A
Hyperlipoproteinemia Type IIb Substitution Non-Coding 2kb upstream

Unknown, but predicted benign in silico (PHRED-scaled CADD = 6).

Abou Khalil et al., 2022
c.-233G>C
Hyperlipoproteinemia Type IIa Substitution Non-Coding 2kb upstream

Unknown, but predicted benign in silico (PHRED-scaled CADD = 10).

Abou Khalil et al., 2022
c.-105A>G
Hyperlipoproteinemia Type IIb Substitution Non-Coding 2kb upstream

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 23).

Abou Khalil et al., 2022
c.-81G>A
(rs766215051)
Hyperlipoproteinemia Type IIa Substitution Substitution | Non-Coding Exon 1, 5' UTR

Unknown, but its PHRED-scaled CADD score (14) did not reach the commonly used threshold of 20 for predicting deleteriousness.

Abou Khalil et al., 2022
c.-78C>G
(rs750782549)
Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb Substitution Substitution | Non-Coding Exon 1, 5' UTR

Unknown, but its PHRED-scaled CADD score (15) did not reach the commonly used threshold of 20 for predicting deleteriousness.

Abou Khalil et al., 2022
c.-24+38G>A
(rs373985746)
Alzheimer's Disease Substitution Substitution | Non-Coding Intron 1

Unknown, but predicted benign in silico (PHRED-scaled CADD =10).

Yee et al., 2021
c.-24+69C>G
(rs440446, +113C/G, IE1, IVS1+69, +969)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Non-Coding Intron 1

Modified APOE transcription.

Mui et al., 1996
c.-24+288G>A
(rs192348494)
Alzheimer's Disease Substitution Substitution | Non-Coding Intron 1

Unknown, but predicted benign in silico (PHRED-scaled CADD =12).

Yee et al., 2021
c.-23-377A>G
(rs150375400)
Alzheimer's Disease Substitution Substitution | Non-Coding Intron 1

Unknown, but predicted benign in silico (PHRED-scaled CADD =10).

Yee et al., 2021
c.-23-280C>T
(rs769448)
Blood Lipids/Lipoproteins Substitution Substitution | Non-Coding Intron 1

Unknown, but predicted to modify APOE transcription.

Radwan et al., 2014
W5Ter
(p.W5*, p.Thr5*)
Alzheimer's Disease, Blood Lipids/Lipoproteins Substitution Substitution | Nonsense Coding Exon 2

Predicted to abrogate production of ApoE as it introduces a stop codon in the signal peptide. PHRED-scaled CADD = 35.

Leren et al., 2016
L8Ter
(p.L8*)
Alzheimer's Disease Substitution Substitution | Nonsense Coding Exon 2

Predicted to eliminate functional ApoE expression. 

Chemparathy et al., 2024
T11S
Alzheimer's Disease, Blood Lipids/Lipoproteins, Dementia Substitution Substitution | Missense Coding Exon 2

Unknown, but predicted benign in silico (PHRED-scaled CADD = 0.6).

Rasmussen et al., 2020
T11A
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 2

Unknown, but predicted benign in silico (PHRED-scaled CADD = 0.3).

Abou Khalil et al., 2022
c.43+11G>A
(rs770658351)
Hyperlipoproteinemia Type IIb Substitution Substitution | Non-Coding Intron 2

Unknown, but its PHRED-scaled CADD score (13) did not reach the commonly used threshold of 20 for predicting deleteriousness.

Abou Khalil et al., 2022
c.43+64C>T
(rs143063029)
Substitution Substitution | Non-Coding Intron 2

Unknown, but predicted benign in silico (PHRED-scaled CADD=4.94).

Chakraborty and Kahali, 2023
c.43+78G>A
(rs769449)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Non-Coding Intron 2

Unknown, but may modify APOE transcription.

Ridker et al., 2008
c.43+219_43+221dupGTT
(rs374670655)
Alzheimer's Disease Duplication Duplication | Non-Coding Intron 2

Unknown.

Yee et al., 2021
c.43+349G>A
(rs61357706, APOE2269)
Blood Lipids/Lipoproteins Substitution Substitution | Non-Coding intron 2

Unknown, but predicted benign in silico (PHRED-scaled CADD = 6).

Radwan et al., 2014
c.43+520G>A
(rs769450, Int2 G/A)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Non-Coding Intron 2

Unknown, but predicted benign in silico (PHRED-scaled CADD = 4).

He et al., 2009
c.44-523G>C
(rs1021908335)
Alzheimer's Disease Substitution Substitution | Non-Coding Intron 2

Unknown, but predicted benign in silico (PHRED-scaled CADD =0.7).

Yee et al., 2021
c.44-469A>G
(rs115299243)
Blood Lipids/Lipoproteins Substitution Substitution | Non-Coding Intron 2

Unknown, but predicted benign in silico (PHRED-scaled CADD = 6).

Radwan et al., 2014
c.44-1G>C
Hyperlipoproteinemia Type IIa Substitution Splicing Alteration | Deletion Non-Coding Intron 2

Unknown, but predicted to alter splicing; predicted damaging in silico (PHRED-scaled CADD = 33).

Abou Khalil et al., 2022
A18T
Alzheimer's Disease, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 3

Predicted to disrupt signal peptide cleavage and affect ApoE secretion. PHRED-scaled CADD = 22.

Zhou et al., 2018;
Yee et al., 2021
E21K (E3K)
(ApoE5)
Multiple Conditions Substitution Substitution | Missense Coding Exon 3

Increased receptor binding in cell-based LDL competition assay; no effect on heparin binding.

Yamamura et al., 1984;
Tajima et al., 1988
A23V (A5V)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 3

Decreased plasma ApoE levels.

Rasmussen et al., 2020
A23A (A5A)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIb Substitution Substitution | Silent Coding Exon 3

Unknown, but predicted benign in silico (PHRED-scaled 3.7).

Radwan et al., 2014
E27fs (E9fs)
Blood Lipids/Lipoproteins, Kidney Disorder: Nephrotic Syndrome Deletion Deletion | Frame Shift Coding Exon 3

Unknown, predicted to be degraded by nonsense-mediated mRNA decay.

E31K (E13K)
(ApoE5 French-Canadian, ApoE4 Philadelphia)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 3

Unknown. In heparin-binding site, but predicted benign in silico (PHRED-scaled CADD = 12).

Mailly et al., 1991
W38Ter (W20Ter)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Substitution | Nonsense Coding Exon 3

Predicted to produce a truncated protein and/or low levels of ApoE, but ApoE levels in carriers were not consistently lower; PHRED-scaled CADD = 29.

Feussner et al., 1998
Q39Ter (Q21Ter)
(p.Q39*)
Alzheimer's Disease Substitution Substitution | Nonsense Coding Exon 3

Predicted to eliminate functional APOE expression.

Chemparathy et al., 2024
R43C (R25C)
(Kyoto, ApoE2 Kyoto)
Multiple Conditions Substitution Substitution | Missense Coding Exon 3

Altered receptor binding, increased aggregation.

Matsunaga et al., 1999
L46P (L28P)
(ApoE4 Freiburg, ApoE4 Pittsburgh)
Alzheimer's Disease, Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 3

Increased Aβ uptake in neurons, increased reactive oxygen species, reduced cell viability. Altered HDL metabolism. Unstable, abnormal structure, more prone to proteolysis.

Kamboh et al., 1999;
Orth et al., 1999
G49fs (G31fs)
Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 3

Eliminates protein, likely by nonsense-mediated decay of mRNA.

Feussner et al., 1992
R50C (R32C)
Substitution Substitution | Missense Coding Exon 3

Unknown, but PHRED-scaled CADD score predicted deleterious (25.3).

Pires et al., 2017
R50H (R32H)
Cardiovascular Disease, Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 3

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Li et al., 2022
T60A (T42A)
(ApoE3 Freiburg)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 3

Unknown, did not reach deleterious threshold in silico (PHRED-scaled CADD = 15).

Wieland et al.,
Q64H (Q46H)
Alzheimer's Disease Substitution Substitution | Missense Coding Exon 3

Unknown, but predicted damaging (PHRED-scaled CADD = 23.3).

Yee et al., 2021
c.236+50T>C
(rs12982192)
Alzheimer's Disease Substitution Splicing Alteration | Non-Coding Intron 3

Modified APOE transcription.

Dieter and Estus, 2010
c.237-33C>G
Hyperlipoproteinemia Type III Substitution Substitution | Non-Coding Intron 3

Unknown, but in silico algorithms predicted it is non-deleterious (PHRED-scaled CADD = 11.42). 

Bea et al., 2023
c.237-28C>T
(rs372675300)
Alzheimer's Disease Substitution Substitution | Non-Coding Intron 3

Unknown, but predicted benign in silico (PHRED-scaled CADD = 2.79).

Yee et al., 2021
c.237-1A>G
(3592 A>G)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Splicing Alteration | Non-Coding intron 3

Disrupted splicing resulting in near abrogation of ApoE expression.

Ghiselli et al., 1981;
Cladaras et al., 1987
D83D (D65D)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 0.6).

Abou Khalil et al., 2022
E84Ter (E66Ter)
(p.E84*)
Progressive Supranuclear Palsy Substitution Substitution | Nonsense Coding Exon 4

Predicted to abrogate ApoE full-length synthesis introducing an early stop codon.

Chemparathy et al., 2024
K90E (K72E)
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 22).

Evans et al., 2013
E98fs (E80fs)
(E97fs)
Alzheimer's Disease, Cardiovascular Disease, Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Eliminates expression of ApoE protein.

Mak et al., 2014
Q99K (Q81K)
(ApoE5 Frankfurt)
Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

Unknown, but in silico prediction did not reach commonly used threshold for deleteriousness (PHRED-scaled CADD = 19).

Ruzicka et al., 1993
P102T (P84T)
Substitution Substitution | Missense Coding Exon 4

Unknown, but PHRED-scaled CADD score predicted deleterious (22.5).

Pires et al., 2017
P102L (P84L)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 23).

Abou Khalil et al., 2022
P102R (P84R)
(ApoE5)
Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

No effect on receptor binding detected, but predicted deleterious by wide variety of in silico algorithms.

Wardell et al., 1991
A104A (A86A)
(A104=, A86=)
Hyperlipoproteinemia Type IV Substitution Substitution | Silent Coding Exon 4

Unknown, but in silico algorithms predicted it is non-deleterious (PHRED-scaled CADD = 1.10).

Bea et al., 2023
R108W (R90W)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown. In silico predictions were inconsistent, but PHRED-scaled CADD score (23.6) suggests deleteriousness.

Bea et al., 2023
R110P (R92P)
Blood Lipids/Lipoproteins, Pancreatitis Substitution Substitution | Missense Coding Exon 4

Unkown, but in silico algorithm predicted deleterious (PHRED-CADD = 24.6).

Abedi et al., 2023
E114K (E96K)
Alzheimer's Disease, Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but carriers had reduced ApoE levels in plasma.

Rasmussen et al., 2020
E114fs (E96fs)
(ApoE3 Groningen)
Hyperlipoproteinemia Type III Insertion Insertion | Frame Shift Coding Exon 4

Predicted to result in a truncated ApoE species or in elimination of its production.

Dijck-Brouwer et al., 2005
R121W (R103W)
Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious (PHRED-scaled CADD = 26.1).

Bea et al., 2023
A124V (A106V)
(ApoE3 Basel)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

No effect on receptor binding, internalization, or degradation.

Miserez et al., 2003
C130R (C112R)
(ApoE4)
Alzheimer's Disease, Multiple Conditions Allele Allele | Allele Coding Exon 4

Strongest known risk factor for AD. Implicated in Aβ and tau pathologies, as well as in multiple other neuronal and non-neuronal functions.

Weisgraber et al., 1981;
Zannis and Breslow, 1981
R132C (R114C)
(Tsukuba)
Splenomegaly Substitution Substitution | Missense Coding Exon 4

Enhanced aggregation, destabilized protein.

Hagiwara et al., 2008
R132S (R114S)
Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico by multiple algorithms.

Pires et al., 2017
R132P (R114P)
Cardiovascular Disease, Diabetes Mellitus Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 25).

Stephens et al., 2005
Y136H (Y118H)
Blood Lipids/Lipoproteins Coding Exon 4

Unknown, but in silico algorithms predicted it is deleterious (PHRED-scaled CADD = 24.8)

Bea et al., 2023
R137C (R119C)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 26).

Abou Khalil et al., 2022
R137H (R119H)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 22).

Abou Khalil et al., 2022
G145D (G127D)
(ApoE1 Bethesda)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 4

Decreased heparin binding and altered b-VLDL binding (LRP receptor), with no apparent effect on LDL binding.

Weisgraber et al., 1984;
Gregg et al., 1983
G145InsEVQAMLG (G127InsEVQAMLG)
(Leiden)
Hyperlipoproteinemia Type III Duplication Duplication | Duplication Coding Exon 4

Reduced receptor binding, heparin binding, HSPG-LPL binding, and lipolysis; increased preference for VLDL.

Wardell et al., 1989;
van den Maagdenberg et al., 1989;
Havekes et al., 1986
R152W (R134W)
Substitution Substitution | Missense Coding Exon 4

Unknown, but PHRED-scaled CADD score predicted deleterious (23.3).

Pires et al., 2017
R152Q (R134Q)
Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

de Knijff et al., 1994
R154fs (R136fs)
(ApoE Australia, ApoE0)
Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Absence of ApoE, at least in VLDL lipoprotein.

Tate et al., 2001
R154S (R136S)
(Christchurch, ApoE2-Christchurch, APOE3 Christchurch)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 4

Reduced receptor and HSPG binding; reduced amyloid-β aggregation, tau phosphoryation. In mice, reduced Aβ-induced tau seeding and spreading possibly via microglia. In APOE4 context, reduced tauopathy, neurodegeneration, and neuroinflammation in mice and iPSCs.

Wardell et al., 1987;
Emi et al., 1988
R154C (R136C)
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 4

Reduced receptor binding.

Walden et al., 1994
R154H (R136H)
Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Moderately reduced receptor and heparin binding.

Minnich et al., 1995
L155F (L137F)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 6).

Abou Khalil et al., 2022
K161_R165del (K143_R147del)
Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy Deletion Deletion | Deletion Coding Exon 4

Unknown, but expected to alter receptor binding and heparin binding.

Xie et al., 2019
R160S (R142S)
Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 26).

Sakuma et al., 1995;
Sakuma et al., 2014
R160C (R142C)
(ApoE1 Nagoya)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Reduced receptor binding and especially heparin binding. Increased prevalence in VLDLs. Multiple effects on lipid and lipoprotein profiles in mice.

Rall et al., 1989;
Havel et al., 1983
R160L (R142L)
Cardiovascular Disease, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 28).

Richard et al., 1995;
Richard et al., 1994
V153_R160dup (V135_R142dup)
(ApoE5ss)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IV Duplication Duplication | Duplication Coding Exon 4

Unknown, but alters the receptor binding and main heparin binding regions.

Yamanouchi et al., 2001
L162_K164del (L144_K146del)
(Tokyo/Maebashi, ApoE Tokyo, ApoE Maebashi, L141_K143del, R142_L144del, K143_R145del)
Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy Deletion Deletion | Deletion Coding Exon 4

Unknown, but expected to alter receptor binding and heparin binding.

Konishi et al., 1999;
Ogawa et al., 2000;
Maruyama et al., 1997
R163C (R145C)
(ApoE4 Philadelphia, ApoE Qatar, APOE ε3[R145C])
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 4

Reduced heparin binding and moderately reduced receptor binding.

Rall et al., 1982
R163H (R145H)
(ApoE Kochi)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Suehiro et al., 1990
R163P (R145P)
(Sendai)
Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Reduced receptor and heparin binding in vitro. In mice, caused LPG-like renal aggregates, altered lipid/lipoprotein profile in blood, and altered macrophage function.

Oikawa et al., 1991;
Oikawa et al., 1997
K164E (K146E)
(ApoE1 Harrisburg)
Blood Lipids/Lipoproteins, Cardiovascular Disease, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Reduced receptor and heparin binding, and reduced ApoE turnover. May interfere with the coordination between lipid association and receptor binding.

Mann et al., 1989;
Mann et al., 1995
K164Q (K146Q)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Altered receptor and heparin binding; reduced VLDL lipolysis.

Rall et al., 1983;
Smit et al., 1990
K164_R165delinsNW (K146_R147delinsNW)
(ApoE1 Hammersmith)
Hyperlipoproteinemia Type III Deletion-Insertion Deletion-Insertion | Deletion-Insertion Coding Exon 4

In mice, drastically altered lipid and lipoprotein profiles in blood. May act as dominant-negative receptor ligand and interfere with LPL and LCAT activities.

Hoffer et al., 1996
R165W
Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Reduced binding to LDL receptors.

Bea et al., 2023
R165P (R147P)
(Chicago)
Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Unknown, but showed enhanced binding to glomerular capillaries. Also, induced structural changes resulting in reduced ApoE stability. Predicted to disrupt oligomerization, enhance aggregation, and alter receptor and heparin binding.

Sam et al., 2006
L167del (L149del)
Multiple Conditions Deletion Deletion | Deletion Coding Exon 4

Altered receptor binding, possibly increasing binding affinity. Also altered lipoprotein catabolism, and possibly lipolytic activity.

Nguyen et al., 2000
R168C (R150C)
(ApoE Modena)
Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy, Splenomegaly Substitution Substitution | Missense Coding Exon 4

Unknown, but may induce dimer formation and facilitate entrapment in kidney capillaries. Also, may affect receptor binding.

Russi et al., 2009
R168G (R150G)
(Okayama)
Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Kinomura et al., 2008
R168H (R150H)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Diabetes Mellitus Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Stephens et al., 2005
R168P (R150P)
(ApoE Guangzhou)
Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Luo et al., 2008
D169dup (D151dup)
(ApoE2 Kanto)
Kidney Disorder: Lipoprotein Glomerulopathy Duplication Duplication | Duplication Coding Exon 4

Unknown.

Matsunaga and Saito, 2014
A170P (A152P)
Substitution Substitution | Missense Coding Exon 4

Reduced receptor binding.

McLean et al., 1984
A170D (A152D)
(ApoE Las Vegas)
Kidney Disorder: Lipoprotein Glomerulopathy, Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Aggregation-prone. Reduced helical content, stability, predicted to induce misfolding.

Bomback et al., 2010
L173L (L155L)
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 8).

Abou Khalil et al., 2022
L173P (L155P)
(ApoE Chengdu)
Kidney Disorder: Lipoprotein Glomerulopathy, Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 25).

Wu et al., 2018
Q174_G191del (Q156_G173del)
Kidney Disorder: Lipoprotein Glomerulopathy, Cardiovascular Disease, Blood Lipids/Lipoproteins Deletion Deletion | Deletion Coding Exon 4

Unknown.

Ando et al., 1999
R176C (R158C)
(ApoE2)
Alzheimer's Disease, Multiple Conditions Allele Allele | Allele Coding Exon 4

Protective against AD risk. Effects on both Aβ (direct) and tau (possibly indirect) pathologies. Also implicated in multiple neuronal and non-neuronal functions.

Weisgraber et al., 1981;
Zannis and Breslow, 1981
[R176C];[C130R] ([R158C;C112R])
(ApoE2/4, ApoE4/2)
Alzheimer's Disease, Multiple Conditions Coding Exon 4

When present in the same host, APOE2 appears to partially mitigate APOE4's harmful effects.

Farrer et al., 1997
[C130R;R176C] ([C112R;R158C])
(ApoE3r, ApoE1y)
Blood Lipids/Lipoproteins, Motor Neuron Disease Coding Exon 4

Unknown.

Persico et al., 2004
R176P (R158P)
(Osaka/Kurashiki, ApoE Osaka/Kurashiki, ApoE2 Kurashiki, ApoE Osaka)
Blood Lipids/Lipoproteins, Cardiovascular Disease, Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Unknown, but structural analyses predicted changes affecting lipid and receptor binding.

Tokura et al., 2011;
Mitani et al., 2011
L177P (L159P)
(ApoE3 Seongnam)
Alzheimer's Disease Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 24) with structual consequences.

Bagaria et al., 2022
V179A (V161A)
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 24).

Abou Khalil et al., 2022
A184fs (A166fs)
(166delG)
Diabetes Mellitus Deletion Deletion | Frame Shift Coding Exon 4

Unknown, but reduced plasma ApoE levels.

Stephens et al., 2005
A184D (A166D)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 23).

Kim et al., 2020
R185R (R167R)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 7).

Abou Khalil et al., 2022
G191C (G173C)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Reduced affinity for LDL receptors in vitro.

Bea et al., 2023
R198C (R180C)
(ApoE1 Baden)
Hyperlipoproteinemia Type IV, Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 26).

Hoffmann et al., 2001
E204Ter (R186Ter)
Hyperlipoproteinemia Type IIa Substitution Substitution | Nonsense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 37).

Sánchez et al., 2021
Q205E (Q187E)
(ApoE2 Toranomon)
Hyperlipoproteinemia Type III, Cardiovascular Disease, Kidney Disorder Substitution Substitution | Missense Coding Exon 4

Receptor and heparin binding appeared to be similar to those of wildtype ApoE3 protein.

Okubo et al., 1998
R207C (R189C)
Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted deleterious in silico (PHRED-scaled CADD = 25).

Zhou et al., 2018
T212S (T194S)
Hyperlipoproteinemia Type III | Missense Coding Exon 4

Unknown, but predicted benign in silico. May affect binding of ApoE to Ab.

Evans et al., 2013
V213E (V195E)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but its PHRED-scaled CADD score (11) did not reach the commonly used threshold of 20 for predicting deleteriousness.

Abou Khalil et al., 2022
S215C (S197C)
(Toyonaka)
Kidney Disorder, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Unknown, but its PHRED-scaled CADD score was just below the commonly used threshold of 20 to predict deleteriousness (PHRED-scaled CADD = 19.5).

Fukunaga et al., 2017
A217A (A199A)
Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb, Hyperlipoproteinemia Type III Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 7.2).

Abou Khalil et al., 2022
G218C (G200C)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 7).

Abou Khalil et al., 2022
P220L (P202L)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIb Coding Exon 4

Increased affinity for LDL receptors in vitro.

Bea et al., 2023
Q222K (Q204K)
Substitution Substitution | Missense Coding Exon 4

Unable to form homodimers and ApoE-ApoAII complexes, but likely due to its ApoE4 backbone. 

Scacchi et al., 2003;
Corbo et al., 1999;
Corbo et al., 1995
A225T (A207T)
Substitution Substitution | Missense Coding Exon 4

Unknown, but PHRED-scaled CADD score predicted deleterious (20.8).

Pires et al., 2017
A227_E230del (A209_E212del)
Blood Lipids/Lipoproteins, Cardiovascular Disease, Hyperlipoproteinemia Type III Deletion Deletion | Frame Shift Coding Exon 4

Predicted to cause a frameshift introducing a stop codon at amino acid 247. In homozygous form, resulted in near elimination of ApoE protein.

Feussner et al., 1996
W228Ter (W210Ter)
(ApoE3 Washington)
Alzheimer's Disease, Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III Substitution Substitution | Nonsense Coding Exon 4

Generated a truncated protein and, in homozygous form, nearly eliminated ApoE from plasma. In cells, decreased ApoE production and secretion by ~2/3. Lipoprotein and lipid profiles in blood indicated a reduction in hepatic removal of remnant lipoprotein particles.

Lohse et al., 1992
E230K (E212K)
(ApoE5)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Increased heparin binding, while decreasing cellular internalization and degradation in cultured cells.

Feussner et al., 1996
R233G (R215G)
Substitution Substitution | Missense Coding Exon 4

Unknown, but PHRED-scaled CADD score predicted deleterious (23.7).

Pires et al., 2017
R235W (R217W)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 25).

Marduel et al., 2013
R242Q (R224Q)
(ApoE2 Fukuoka)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Binding to LDL cell surface receptors and heparin was similar to wildytpe ApoE3.

Moriyama et al., 1996
R246C (R228C)
(ApoE2 Dunedin)
Hyperlipoproteinemia Type IV, Hyperlipoproteinemia Type V Substitution Substitution | Missense Coding Exon 4

Receptor-binding activity was normal in a competitive binding assay.

Wardell et al., 1990;
Nye et al., 1986
D248Y (D230Y)
(ApoE Hong Kong)
Kidney Disorder: Lipoprotein Glomerulopathy Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 27).

Cheung et al., 2009
E249K (E231K)
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 4

Unknown; its PHRED-scaled CADD score (19.7) was very close to the commonly used threshold of 20 for predicting deleteriousness.

Abou Khalil et al., 2022
E252K (E234K)
Hyperlipoproteinemia Type IIb Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 22).

Abou Khalil et al., 2022
V254E (V236E)
(Jacksonville, APOE3-Jacksonville, APOE3-Jac, APOE ε3 (V236E), APOE*2(Val236-->Glu))
Alzheimer's Disease, Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Reduced ApoE self-oligomerization and promoted lipid metabolism in transgenic mouse brains. Also reported to increase dimerization. In AD mice, reduced plaques and dystrophic neurites.

van den Maagdenberg et al., 1993
E262K (E244K)
Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-CADD = 23.3)

Maeda et al., 1989;
Yamamura et al., 1984
E262_E263delinsKK (E244_E245delinsKK)
(Suita, ApoE7 Suita)
Multiple Conditions Deletion-Insertion Deletion-Insertion | Deletion-Insertion Coding Exon 4

Unclear, but predicted damaging by multiple in silico algorithms.

Maeda et al., 1989;
Yamamura et al., 1984
E263K (E245K)
Cerebral Palsy, Blood Lipids/Lipoproteins, Cardiovascular Disease Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-CADD = 23.9)

Maeda et al., 1989;
Yamamura et al., 1984
I268M (I250M)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but did not reach commonly used in silico threshold for deleteriousness (PHRED-scaled CADD = 9).

Sánchez et al., 2021
R269G (R251G)
(ApoE ε4 (R251G))
Alzheimer's Disease, Multiple Conditions Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 23).

van den Maagdenberg et al., 1993
R269H (R251G)
Hyperlipoproteinemia Type IIa Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 25).

Diboun et al., 2022
L270E (L252E)
Hyperlipoproteinemia Type IIa Deletion-Insertion Deletion-Insertion | Missense Coding Exon 4

Unknown.

van den Maagdenberg et al., 1993
R292H (R274H)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted damaging in silico (PHRED-scaled CADD = 25).

van den Maagdenberg et al., 1993
W294C (W276C)
Substitution Substitution | Missense Non-Coding Exon 4

Unknown, but predicted to alter ApoE structure by in silico analyses.

Pires et al., 2017
S314R (S296R)
Blood Lipids/Lipoproteins Substitution Substitution | Missense Coding Exon 4

Unknown, but predicted benign in silico (PHRED-scaled CADD = 11).

van den Maagdenberg et al., 1993
c.*25C > T
(rs374329439)
Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb Substitution Substitution | Non-Coding Exon 4, 3' UTR

Unknown, but predicted benign in silico (PHRED-scaled CADD = 6).

Abou Khalil et al., 2022;
Radwan et al., 2014
c.*36C > G
Hyperlipoproteinemia Type IIa Substitution Substitution | Non-Coding Exon 4, 3' UTR

Unknown, but predicted benign in silico (PHRED-scaled CADD = 7).

Abou Khalil et al., 2022
c.*92C>T
(rs553874843)
Alzheimer's Disease Substitution Substitution | Non-Coding Exon 4, 3' UTR

Unknown, but predicted benign in silico (PHRED-scaled CADD = 1.25).

Yee et al., 2021