Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP2, PP3, BS1, BS2, BS4
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr14:73673178 A>G
dbSNP ID: rs17125721
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9


This variant was initially found in people with early onset AD (e.g., Taddei et al., 2002; Albani et al., 2007); however, it did not segregate with disease. It was also identified in individuals with late-onset AD and in healthy controls (e.g., Mattila et al., 1998; Dermaut et al., 1999; Aldudo et al., 1998; Zekanowski et al., 2004; Helisalmi et al., 2000; Perrone et al., 2020). It is present in the gnomAD variant database at a frequency of 0.01487 with an allele count of 4,197 (gnomAD v2.1.1, August 2021). Moreover, in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, the frequency is 0.022 (HEX, August 2020). Also, the larger of two association studies, including nearly 500 AD cases and 3,000 controls, failed to reveal a link between the variant and AD risk. 

In a study of individuals of Spanish descent, this variant was detected in two of 176 individuals with AD and three of 139 controls (Jin et al., 2012). The cases with AD were described as having sporadic early onset AD, with onset at 56.5 and 65.5 years of age. Further clinical details were not reported. The presence of this variant in controls led the authors to classify the variant as not pathogenic. 

The E318G variant was later found in about 5 percent of families affected by familial late onset AD (30 out of 565 families). The variant was more frequently found in cases of familial late-onset AD than in cases of "sporadic" late-onset AD (Benitez et al., 2013). This mutation also turned up in a study that sequenced AD-associated genes in people with extreme biomarker levels of in their cerebrospinal fluid (Benitez et al., 2013; Sep 2013 news). Specifically, the E318G variant was associated with high levels of total tau and phospho-tau. In APOE4 carriers it was also associated with Aβ deposition and faster cognitive decline. Furthermore, at least two studies reported that APOE4 carriers who also carried the E318G variant were at greater risk of developing late-onset AD, than APOE4 carriers without the variant (Benitez et al., 2013; Nho et al., 2016). In addition, in a study of 72 AD cases and 58 controls, the E318G variant was detected in one individual with AD and in one control, the latter lacking significant AD neuropathology postmortem. Additional information regarding these two mutation carriers, including their ages, was not reported (Frigerio et al., 2015). 

Subsequently, a study of two Brazilian cohorts, including 53 individuals with a familial history of AD and 120 with sporadic AD, concluded that the E318G variant increases AD risk (Abdala et al., 2017). In familial AD cases, the odds ratio was 6.0 (IC95%=1.06-33.79; p=0.042). However, a larger study of 3420 American individuals, including 478 diagnosed with AD, found no significant association (Hippen et al., 2016). In this study, a Fisher's exact test suggested APOE4 carriers with an E318G allele had a slighly higher risk of AD than those without the allele, but the effect did not reach statistical significance. LIkewise, a logistic regression model found a positive, but non-significant E318G effect. Neither study found an interaction between E318G and APOE4. Similarly, a study of Belgian individuals identified the variant in 45 of 1,431 AD patients and in 24 of 809 controls. An association with AD was not detected, regardless of APOE genotype (Perrone et al., 2020).

The E318G variant has also been implicated in increasing the risk of dementia with Lewy bodies. In a cohort of 111 pathologically confirmed cases of this disease, 10 individuals carried the mutation, a frequency much higher than seen in controls (Geiger et al., 2016).


At least one mutation carrier lacked AD neuropathology (Frigerio et al., 2015).

Biological Effect

Studies of the biomarker profiles of E318G carriers have yielded mixed results. Although one study reported increased tau and phospho-tau levels in CSF from carriers (Benitez et al., 2013), no changes in these CSF biomarkers, nor in Aβ42, were found in asymptomatic members of a large Italian family, although plasma Aβ40 levels were increased (Artuso et al., 2019). A more recent study of 20 Belgian carriers found a reduction in both Aβ42 and Aβ43 CSF levels, with a decrease in the Aβ43/Aβ42, Aβ43/Aβ40, and Aβ42/Aβ40 ratios (Perrone et al., 2020). Interestingly, in this study, the CSF profiles of E318G carriers shared similarities with those of known pathogenic mutation carriers, as well as with those of controls. In particular, carriers of known pathogenic mutations or E318G could be distinguished from controls based on their CSF Aβ43 and Aβ42 levels, which positively correlated with each other. However, Aβ43 and Aβ42 levels correlated with Aβ40 in both E318G carriers and controls, but not in carriers of known pathogenic mutations. Also, CSF sAPPα and sAPPβ levels were reduced in E318G carriers, as were Aβ43/sAPPα and Aβ43/sAPPβ ratios. Although similar alterations were observed in pathogenic mutation carriers, they failed to reach statistical significance. The biological meaning of these reductions remains unclear given that sAPPα and sAPPβ are generated by α- and β-secretase, rather than γ-secretase.

In vitro experiments have also yielded mixed results. In HEK293 cells transfected with PSEN1 E318G, secretion of both Aβ40 and Aβ42 peptides was reported as robustly increased compared to controls (Bialopiotrowicz et al., 2012). However, in mouse neuroblastoma cells, neither Aβ42 levels nor the Aβ42/Aβ40 ratio were found to be increased (Hsu et al., 2020). In experiments using isolated proteins, Aβ40 and Aβ42 production was reduced to undetectable levels (Sun et al., 2017). 

Several in silico algorithms (LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, REVEL, and Reve in the VarCards database) yielded conflicting predictions regarding the effects of this variant (Xiao et al., 2021), but the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Using their pathogencity guidelines, Hsu and colleagues classified E318G as "not pathogenic" (Hsu et al., 2020).




Alzheimer's Disease : Benign*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

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


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.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 


Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.


Lack of segregation in affected members of a family.

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

Last Updated: 22 Feb 2022


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News Citations

  1. Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

Paper Citations

  1. . Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population. Mol Psychiatry. 2002;7(7):776-81. PubMed.
  2. . Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population. Neurobiol Aging. 2007 Nov;28(11):1682-8. PubMed.
  3. . The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease. Ann Neurol. 1998 Dec;44(6):965-7. PubMed.
  4. . The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet. 1999 Jan;64(1):290-2. PubMed.
  5. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.
  6. . The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort. Neurosci Lett. 2004 Mar 11;357(3):167-70. PubMed.
  7. . Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?. Neurosci Lett. 2000 Jan 7;278(1-2):65-8. PubMed.
  8. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  9. . Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
  10. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  11. . Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease. BMC Med Genomics. 2016 Aug 12;9 Suppl 1:30. PubMed.
  12. . Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil. Neurosci Lett. 2017 Jul 13;653:341-345. Epub 2017 May 26 PubMed.
  13. . Presenilin E318G variant and Alzheimer's disease risk: the Cache County study. BMC Genomics. 2016 Jun 29;17 Suppl 3:438. PubMed.
  14. . Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016 Oct;94:55-62. Epub 2016 Jun 14 PubMed.
  15. . Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer's disease in a Family with Late-onset Dementia. Curr Alzheimer Res. 2019;16(1):1-7. PubMed.
  16. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
  17. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  18. . 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.
  19. . 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.

Other Citations

  1. HEX

External Citations

  1. gnomAD v2.1.1, August 2021
  2. CADD v.1.6

Further Reading


  1. . Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch Neurol. 2005 Oct;62(10):1624-7. PubMed.
  2. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  3. . Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V. Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):184-7. PubMed.
  4. . Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008 Apr;255(4):604-6. Epub 2008 Mar 25 PubMed.
  5. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.
  6. . Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 2016 Sep 19; PubMed.
  7. . Atypical Huntington's disease with the clinical presentation of behavioural variant of frontotemporal dementia. J Neural Transm (Vienna). 2016 Dec;123(12):1423-1433. Epub 2016 Jun 10 PubMed.
  8. . Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity. Front Neurol. 2020;11:596108. Epub 2020 Nov 30 PubMed.

Protein Diagram

Primary Papers

  1. . Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996 Aug;40(2):265-6. PubMed.
  2. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  3. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.


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