Pathogenicity: Alzheimer's Disease : Uncertain Significance, Frontotemporal Dementia : Not Classified
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia
Reference Assembly: GRCh37/hg19
Position: Chr1:227075798 C>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAT to AAT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7


This mutation has been found in several individuals of East Asian ancestry. Its global frequency in the gnomAD variant database is relatively low (0.0001874), but all 53 heterozygote carriers reported are of East Asian ancestry, bringing the frequency in this population up to 0.002656 (gnomAD v2.1.1, Nov 2021).

The variant was first identified in two unrelated Chinese individuals, one affected by familial late-onset Alzheimer’s disease and the other by apparently sporadic frontotemporal dementia. Segregation with disease was not established (Shi et al., 2015). One mutation carrier experienced progressive memory loss starting at age 68. She met clinical criteria for probable AD. Her APOE genotype was E3/E4. Her brother developed dementia at age 64 and died at 66. The other mutation carrier had apparently sporadic FTD. At age 62, he developed behavioral changes and progressive language disturbance, including word-finding difficulty, nonfluent and sparse speech, and stuttering. His symptoms were consistent with Progressive Nonfluent Aphasia (PNFA), a subtype of primary progressive aphasia (PPA). In addition, he became withdrawn and apathetic, and later developed global cognitive impairment.

The mutation was subsequently found in a Chinese patient diagnosed with AD at age 59 (Xu et al., 2018), and a Korean woman with early onset AD who developed cognitive decline, memory problems, and language impairment starting at age 59 (Giau et al., 2019). 


Unknown. Neuroimaging of one of the AD cases showed diffuse cortical atrophy, especially in the bilateral temporal lobe (Shi et al., 2015). FDG-PET showed hypometabolism in bilateral frontal lobe, lateral temporal lobe, parietal lobe, and insular cortex, in addition to the cingulate cortex, precuneus, and caudate nucleus. PIB-PET showed amyloid deposition in the bilateral frontal lobe, lateral temporal lobe, parietal lobe, cingulate cortex, and precuneus.

Neuroimaging in the mutation carrier with FTD showed mild symmetrical cerebral atrophy. FDG-PET showed hypometabolism in the left frontal cortex, anterior cingulate cortex, thalamus, and caudate nucleus. He was amyloid-negative by PIB-PET.

Biological Effect

The biological effects of this variant are unknown, but most in silico algorithms tested predicted a damaging effect (Xu et al., 2018, Giau et al., 2019) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Nov 2021).

Last Updated: 04 Nov 2021


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Paper Citations

  1. . Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.
  2. . The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
  3. . Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.


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