Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3, BS4
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Reference Assembly: GRCh37/hg19
Position: Chr1:227071475 C>T
dbSNP ID: rs140501902
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5


This PSEN2 variant has been found in both cognitively healthy individuals and patients with Alzheimer's disease. It was reported in more than a thousand individuals, most of European ancestry, in the gnomAD variant database (allele frequency = 0.003711, gnomAD v2.1.1, Nov 2021), and at a similar frequency 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 (Nov 2021).

It has also been reported in a handful of individuals diagnosed with early onset, as well as those with late-onset, AD. Although some of these variant carriers have a family history of dementia, the variant does not appear to segregate with disease. It has been shown not to segregate in at least one family. Although not thought to be a causative mutation, R71W may be a disease modifier.

The R71W variant was first identified in a Caucasian patient with late-onset Alzheimer's disease. In the same study, it was also found in one of 283 healthy controls (Sleegers et al., 2004). The R71W variant was subsequently reported in two more patients with late-onset AD (Brouwers et al., 2008; Guerreiro et al., 2010).

The R71W variant was also found in a woman from Macedonia who developed apparently sporadic AD at the age of 64. Her symptoms were described as fairly typical of AD, with the addition of a hand tremor. She had no known family history of dementia, but her mother had died at age 20 from tuberculosis, and information relating to the maternal line was unknown (Lohmann et al., 2012).

This variant was also found in a large French study reporting 56 families with a putative familial form of Alzheimer disease (Wallon et al., 2012). The R71W variant was detected in two families, EXT 075 and EXT 179. Both probands met NINCDS-ADRDA criteria for probable AD. In the EXT 075 family, both affected family members screened were mutation carriers, suggesting possible segregation with disease. Ages at onset were 63 and 64 years, with a disease duration of six to nine years. In the EXT 179 family, only the proband was a known carrier of R71W; DNA was not available from family members, including three affected relatives, so segregation with disease could not be determined. Onset in this family was 55 to 56 years of age, with a disease duration of seven to 16 years.

Another recent study detected the R71W variant in six families with a history of familial late-onset AD, but the mutation did not segregate with disease. Specifically, it was found in six affected individuals and three healthy individuals. In addition, it was absent in eight affected family members, arguing against pathogenicity. The authors noted that the R71W mutation was associated with an earlier age at onset, 70.2 years versus 76.7 years in non-carriers, suggesting that R71W may be a disease modifier (Cruchaga et al., 2012).

This variant was also reported in an individual with idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual developed symptoms at age 65, starting with resting tremor. Later symptoms included bradykinesia, rigidity, postural instability, and dementia over a 10–year disease course. It was unclear what role, if any, the R71W variant played in disease pathogenesis.

In a study using whole-exome sequencing, this variant was identified in two of 424 French people with early onset AD (Nicolas et al., 2015). Associated clinical data were sparse for these individuals. One had apparently sporadic AD, with onset at age 60 and an APOE genotype of E3/E3. The other individual had a family history of AD, although segregation of the R71W variant could not be assessed. Onset in this individual occurred at age 65 and APOE genotype was E3/E4.

An Italian woman suffering from apathy and short-term memory loss in her early 60s, with a family history of memory impairment, was also found to carry this variant (Coppola et al., 2021).


Unknown. Neuroimaging data were available for two mutation carriers. One with late-onset AD was described as having leukoencephalopathy with periventricular white-matter lacunar infarctions (Guerreiro et al., 2010). Another with memory impairment had diffuse supratentorial white matter hypodensity, and 18FDG-PET revealed mild hypometabolism predominantly in the left hemisphere, including the mesial and lateral temporal cortex, the dorsolateral/medial frontal cortex, and to a lesser extent the posterior cingulate cortex (Coppola et al., 2021). Diffuse amyloid deposition revealed by AMY-PET was also reported.

Biological Effect

This variant did not affect the ratio of Aβ42/Aβ40 in cellular assays using HEK293 cells or mouse neuroblastoma cells (To et al., 2006, Hsu et al., 2020). However, it has been shown to reduce the stability of the presenilin-2 protein and to impair Notch signaling (To et al., 2006). In silico, this variant is predicted to be probably damaging by Poly-Phen2 (Cruchaga et al., 2012), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).


Alzheimer's Disease : Benign*

*This variant may be a disease modifier, 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.


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.  R71W: Most carriers were 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. R71W: Although this variant did not alter the Aβ42/Aβ40 ratio in cellular assays, it destabilized PSEN2.


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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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. . Molecular genetics of Alzheimer's disease: an update. Ann Med. 2008;40(8):562-83. PubMed.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  4. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  5. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  6. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. Epub 2012 Feb 1 PubMed.
  7. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  8. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  9. . Singular cases of Alzheimer's disease disclose new and old genetic "acquaintances". Neurol Sci. 2020 Oct 2; PubMed.
  10. . Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene. 2006 Jun 15;25(25):3557-64. PubMed.
  11. . 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. HEX

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.


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