Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683855 G>C
dbSNP ID: rs63750646
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11


This mutation was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/B, included at least 16 affected individuals over five generations. The mutation was shown to segregate with disease: three affected siblings carried the mutation, while three unaffected siblings did not. The average age of onset was 35 (34.7 ± 3.0 years). The diagnosis of AD was confirmed in several family members at autopsy. Clinical information related to this family was reported in Martin et al., 1991.

A Japanese family with this mutation has also been identified (Tanahashi et al., 1996). This family, known as FAD-Yg, included four family members affected by early onset AD. Symptom onset ranged from 31 to 37 years old. Two family members had postmortem confirmed AD.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).


Neuropathology consistent with AD was observed in members of the AD/B family. In addition to typical AD pathology of cortical plaques and tangles, amyloid plaques were also noted in the cerebellum. Typical AD pathology was observed in at least two members of the FAD-Yg family from Japan (Tanahashi et al., 1996).

Biological Effect

This mutation has been reported to impair the carboxypeptidase-like γ-cleavage, but spare the endoproteolytic ε-cleavage activity of PSEN1 (Li et al., 2016; Murayama et al., 1997). As assessed by in vitro experiments with isolated proteins, it decreases γ-secretase efficiency by 75 percent for both Notch and APP (Chávez-Gutiérrez et al., 2012). Cell-based and in vitro experiments indicate it reduces production of Aβ40 and increases the Aβ42/Aβ40 ratio (DeJonghe et al., 1999; Bentahir et al., 2006; Li et al. 2016; Sun et al., 2017). One study with isolated proteins suggested the mutant slows Aβ40, but not Aβ42, production (Fluhrer et at., 2008).

Consistent with the overall decrease in γ-secretase efficiency, in one cell-based study, all APP peptides measured (AICD, Aβ38, Aβ40, Aβ42, and Aβ43) were decreased, but the relative proportions of Aβ42 and Aβ43 were increased, while those of Aβ38 and Aβ40 were decreased (Kakuda et al., 2021). In line with these observations, several studies observed sizeable reductions in the Aβ38/Aβ42 and Aβ40/Aβ43 ratios, both in cells and in vitro (Chávez-Gutiérrez et al., 2012; Svedružić et al., 2012; Kakuda et al., 2021). These data suggest impairment of the fourth γ-secretase cleavage in the Aβ production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides. A study using mass spectrometry to monitor the tri- and tetra-peptides released by HEK293 cells stably expressing Swedish mtAPP695 and BACE1, and transfected with the PSEN1 G384A mutant, indicated that, indeed, both production lines appear to be disrupted (Li et al., 2016). One alteration may involve enhanced Aβ43 production via the Aβ48 line instead of the Aβ49 line (Kakuda et al., 2021).

Moreover, in vitro assays revealed that mutant γ-secretase activity is more sensitive to increased temperatures than the wild-type protein, suggesting the mutation destabilizes the enzyme-substrate interaction required for sequential Aβ peptide proteolysis, resulting in the release of longer Aβ peptides (Szaruga et al., 2017; Jul 2017 news). A conformational change that affects how the APP substrate is presented to the active site of γ-secretase has been observed using fluorescence lifetime imaging microscopy (Berezovska et al., 2005). Interestingly, two suppressor mutations identified in a yeast model system activated Aβ trimming and reduced Aβ42 production in mouse fibroblasts expressing PSEN1 G384A (Futai et al., 2016).

G384 is located in the GxGD motif, a region considered central to substrate cleavage (Pérez-Revuelta et al., 2010; Steiner et al., 2000). It has been implicated in the interaction of γ-secretase with both APP and Notch, with its amide group donating a conserved H-bond to anchor the transmembrane helix of each substrate (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news). Computational simulations suggest that the replacement of a glycine by an alanine at this site reduces the stability of the protein and favors a more open conformation in which the substrate is held more loosely, resulting in imprecise cleavage and earlier release of longer Aβ peptides (Dehury et al., 2020). 

Additionally, this mutation caused PSEN1 to localize to endolysosomal compartments, similar to the distribution of PSEN2. This resulted in altered substrate specificity and an increased Aβ42/Aβ40 ratio in the intracellular pool of Aβ (Sannerud et al., 2016; see May 2016 news).

G384A may also disrupt other cellular functions relevant to AD. Interestingly, PSEN1 was reported to play a key role in ApoE secretion and cytoplasmic localization. In experiments with PSEN-deficient fibroblasts, G384A transfection was less able to rescue these functions compared with transfection of wildtype PSEN1 (Islam et al., 2022). The G384A mutation may also affect PSEN1's putative activity as a passive calcium leak channel in the endoplasmic reticulum. This activity was reported as abolished in mouse embryonic fibroblasts expressing the mutant protein (Nelson et al., 2007).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).


Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. G384A: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. G384A: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 04 Mar 2022


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News Citations

  1. sAPP Binds GABA Receptor, and More News on APP
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  3. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  4. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  5. . Different effects of Alzheimer-associated mutations of presenilin 1 on its processing. Neurosci Lett. 1997 Jun 20;229(1):61-4. PubMed.
  6. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  7. . Evidence that Abeta42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol Dis. 1999 Aug;6(4):280-7. PubMed.
  8. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  9. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  10. . Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J Biol Chem. 2008 Oct 31;283(44):30121-8. PubMed.
  11. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  12. . Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. PubMed.
  13. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
  14. . Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci. 2005 Mar 16;25(11):3009-17. PubMed.
  15. . Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities. J Biol Chem. 2016 Jan 1;291(1):435-46. Epub 2015 Nov 11 PubMed.
  16. . Requirement for small side chain residues within the GxGD-motif of presenilin for gamma-secretase substrate cleavage. J Neurochem. 2010 Feb;112(4):940-50. Epub 2009 Dec 15 PubMed.
  17. . Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol. 2000 Nov;2(11):848-51. PubMed.
  18. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  19. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  20. . A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
  21. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.
  22. . Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
  23. . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.
  24. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading


  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  2. . Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease. Mol Cell Neurosci. 2015 Jul;67:55-65. Epub 2015 Jun 4 PubMed.
  3. . Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer's disease. Curr Alzheimer Res. 2012 Aug 30; PubMed.
  4. . Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB J. 2012 Jul;26(7):3065-74. PubMed.
  5. . Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure. J Neurochem. 2011 Feb;116(3):385-95. PubMed.
  6. . Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):565-75. PubMed.
  7. . Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):551-64. PubMed.
  8. . DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry. 2006 Mar 28;45(12):3952-60. PubMed.
  9. . BACE1 and mutated presenilin-1 differently modulate Abeta40 and Abeta42 levels and cerebral amyloidosis in APPDutch transgenic mice. Neurodegener Dis. 2007;4(2-3):127-35. PubMed.
  10. . Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
  11. . Immunoreactivity of presenilin-1 and tau in Alzheimer's disease brain. Exp Neurol. 1998 Feb;149(2):341-8. PubMed.
  12. . Proteolytic processing of presenilin-1 in human lymphoblasts is not affected by the presence of the I143T and G384A mutations. Neurosci Lett. 1999 Oct 29;274(3):183-6. PubMed.

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.


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