Mature Protein Numbering: Q46H


Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45411165 G>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs370594287
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to CAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3


This variant was reported in a study in which the APOE genes of 257 Southern Chinese individuals, including 69 AD patients, 83 subjects with mild cognitive impairment (MCI), and 105 cognitively healthy controls, were sequenced (Yee et al., 2021). The variant was found in one AD patient (0.7%) and one control (0.5%).

In the gnomAD variant database, the variant was reported at a global frequency of 0.00014 (gnomAD v2.1.1, Oct 2022). Of 39 heterozygotes, 24 were of East Asian ancestry and 10 of South Asian ancestry, with one South Asian homozygote.

Biological Effect

The biological effect of this variant is unknown, but it may alter interactions between the N- and C-terminal domains of ApoE. An NMR study of an APOE3-like construct harboring multiple mutations to keep it from aggregating, suggested Q64 forms a hydrogen bond with R231 (Chen et al., 2011), an interaction that may be disrupted given that Q64H substitutes an acidic amino acid with a basic one (Yee et al., 2021). A subsequent study using FRET and computational simulations to study monomeric ApoE4 also identified the Q64-R231 interaction but, interestingly, only when the C-terminal domain was undocked from the N-terminal helix bundle, a configuration suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

Interestingly, Q64 was reported to play a role in the formation of ApoE4, but not ApoE2 or ApoE3, dimers (Nemergut et al., 2023). Lipid-free ApoE4 molecules formed V-shaped dimers that fueled aggregation, while ApoE2 and ApoE3 formed less aggregation-prone T-shaped dimers.

Computational modeling predicted the substitution might slightly reduce protein stability, while maintaining local alpha helical structure (Yee et al., 2021). The variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 23.3, above the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, Oct 2022). Moreover, this variant was predicted to be damaging by eight of 16 different algorithms that rely on sequence homology, supervised-learning, protein-sequence and structure, or consensus sequence identification (Pires et al., 2017 see supplementary table 2).

Last Updated: 27 Sep 2023


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Paper Citations

  1. . Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese. Curr Alzheimer Res. 2021 Mar 24; PubMed.
  2. . Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 PubMed.
  3. . Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.
  4. . Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.
  5. . In silico analyses of deleterious missense SNPs of human apolipoprotein E3. Sci Rep. 2017 May 30;7(1):2509. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese. Curr Alzheimer Res. 2021 Mar 24; PubMed.

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