Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr1:227071448 C>T
dbSNP ID: rs150400387
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5


This variant has been reported in several patients with neurodegenerative disease, as well as in two healthy controls. It was first identified in one of 283 control subjects from an Alzheimer’s disease (AD) study in the Netherlands (Sleegers et al., 2004), and subsequently in a healthy first-degree relative of a patient with late-onset AD (Ertekin-Taner et al., 2008).

Carriers with degenerative disease include at least five individuals with AD and one with frontotemporal dementia. Most of the AD carriers had late-onset disease, including two Belgian patients (Brouwers et al., 2008Perrone et al., 2020), a Caucasian individual (Sassi et al., 2014), and a Han Chinese man (Mao et al., 2021).

However, the variant was also reported in a 49-year-old Korean man diagnosed with probable early onset AD (Park et al., 2017; An et al., 2016). His symptoms included memory loss, personality changes including obsessive-compulsive behavior, and disorientation. He was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP. He had no family history of dementia.

In one case, a European carrier with AD whose brother was also affected, age at onset was not reported (Sala Frigerio et al., 2015).

The variant was also identified in a genetic screen of 421 patients in the U.K. with early onset frontotemporal dementia (Koriath et al., 2018).

The variant was present in the gnomAD variant database at a frequency of 0.00022 and an allele count of 62 (gnomAD v2.1.1, Nov 2021). All carriers in gnomAD were heterozygotes, most of European ancestry (43).


Neuropathological data are unavailable, but one carrier had reduced Aβ43 and Aβ42 levels in CSF, and increased Aβ40 levels, resulting in a decreased Aβ42/Aβ40 ratio (Perrone et al., 2020). This carrier also had decreased levels of sAPPα and sAPPβ. In another carrier, mild cortical atrophy was revealed by MRI, and SPECT showed hypoperfusion in the frontal, temporal, and limbic lobes (Park et al., 2017).

Biological Effect

As described above, this variant was associated with reduced Aβ43 and Aβ42, and increased Aβ40, levels in the CSF of one carrier (Perrone et al., 2020). However, Aβ40 and Aβ42 secretion were unaffected in an experimental assay using transfected mouse neuroblastoma cells (Hsu et al., 2020). In silico algorithms predicted the R62C substitution is possibly damaging (PolyPhen) or damaging (SIFT) or neutral (LRT), and R62 is conserved between PSEN1 and PSEN2 (Hsu et al., 2020; Sala Frigerio et al., 2015; Mao et al., 2021). Its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Moreover, structural prediction analyses suggested the variant may cause large conformational alterations (Park et al., 2017).

Hardy and colleagues classified the variant as likely benign (Sassi et al., 2014) and, similarly, Karch and colleagues classified it as not pathogenic (Hsu et al., 2020). However, Mead and co-workers considered it possibly deleterious, predicting it is most likely fully penetrant (Koriath et al., 2018).


Alzheimer's Disease : Benign

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


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.  R62C: Most carriers are of European ancestry.


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.


Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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

Last Updated: 08 Feb 2023


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Paper Citations

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.
  2. . Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology. 2008 Feb 19;70(8):596-606. Epub 2007 Oct 3 PubMed.
  3. . Molecular genetics of Alzheimer's disease: an update. Ann Med. 2008;40(8):562-83. PubMed.
  4. . 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.
  5. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.
  6. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
  7. . A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction. Clin Interv Aging. 2017;12:367-375. Epub 2017 Feb 13 PubMed.
  8. . A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. Clin Interv Aging. 2016;11:1817-1822. Epub 2016 Dec 15 PubMed.
  9. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  10. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Other Citations

  1. Sala Frigerio et al., 2015

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.

Other mutations at this position


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