Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076678 A>G
dbSNP ID: rs28936379
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8


This mutation was first identified in 1995 in a large Italian kindred known as FL010 (Rogaev et al., 1995). This pedigree contains 134 members over five generations. The mode of inheritance is consistent with autosomal-dominant transmission with high penetrance. The clinical course of the disease within the family was highly variable, particularly with respect to age of onset, disease duration, and clinical presentation. Based on data from 15 affected individuals, the mean age of onset was 60.1 ± 10.0 years (45 to 83); the mean age at death was 71.1 ± 9.6 years (range: 59 to 87), and the mean disease duration was 11.3 ± 4.7 years (range: four to 22 years). The common clinical feature for patients in this family was progressive cognitive decline accompanied by various other symptoms, including seizures, depression, aphasia, behavioral disturbances including persecutory delusions, and aggressive behavior and psychomotor agitation (Marcon et al., 2004).

This mutation was also observed in a large French study reporting on 56 families affected by a putative familial form of early onset Alzheimer disease (Wallon et al., 2012). The M239V mutation was detected in five of the 56 probands. DNA from family members was not available for screening, so segregation with disease could not be determined for any of the five families. Clinical data for these families can be summarized as follows. Family ALZ 400: two affected individuals with onset at 47 to 55 years and duration of seven to 13 years. Family TOU 035: five affected individuals with onset at 53 to 62 years and duration of 15 years. Family ALZ 434: five affected individuals with onset at 48 to 67 years and duration of four to 11 years. Family ROU 360: six affected individuals with onset at 49 to 57 years and duration of 10 to 19 years. Family EXT 062: two affected individuals with onset at 47 and 60 years and duration of five and seven years.

In addition, this mutation was identified by whole-exome sequencing in a Frenchman diagnosed with Alzheimer’s disease according to NINDCS-ADRDA criteria (Nicholas et al., 2015). Memory problems developed when he was 53 years old. He was noted to have a biparietal posterior variant of AD. His APOE genotype was E2/E4. He did not have a family history of AD; however, his father died at age 48 so it is unknown whether he would have developed the disease had he lived.

The mutation was also reported in two Chinese studies. In one, a Chinese Han patient diagnosed with early onset familial AD was described (Li et al., 2021). Their initial symptom was memory loss, followed by behavioral and psychological alterations, including personality changes, as well as seizures and slowed motor responses. Two additional family members were affected. It was also reported in a man diagnosed with AD from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced (Jiao et al., 2021). This carrier's age at onset was 53 years and his APOE genotype was APOE E2/E3. He had a family history of AD. Memory loss, language impairment, as well as mental and behavioral changes were reported. Of note, the two publications included authors from the same institution, Xiangya Hospital, so it is possible the carriers were related, or may even be the same individual.

The mutation was absent from the gnomAD variant database (v2.1.1, Nov 2021).


Neuropathological data are available for two affected patients. Diffuse cerebral atrophy was observed in both samples, with senile plaques and neurofibrillary tangles in the neuropil consistent with the diagnosis of definite AD by CERAD criteria. Neurofibrillary pathology was extensive and categorized as stage VI of Braak and Braak. In addition to the characteristic AD lesions, some atypical neuropathologic features were observed, including numerous ectopic neurons in the subcortical white matter that often contained neurofibrillary tangles and numerous extracellular "ghost" neurofibrillary tangles that were immunoreactive for Aβ40 (Marcon et al., 2004).

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the M239V mutation did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. When co-transfected with APP carrying the Swedish mutation, the M239V mutation produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005). Consistently, computer simulations of the structure and function of PSEN2 predicted this variant increases the size of the active site pocket which is expected to increase substrate diffusion resulting in increased Aβ42 and decreased Aβ40 production (Soto-Ospina et al., 2021). Moreover, the mutation's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 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.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. M239V: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M239V: Variant located in the predicted proteolytic active site.


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.


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: 22 Feb 2022


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Paper Citations

  1. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
  2. . Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol. 2004 Mar;63(3):199-209. PubMed.
  3. . 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.
  4. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  5. . Early-onset familial Alzheimer's disease in a family with mutation of presenilin 2 gene. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Feb 28;46(2):189-194. PubMed.
  6. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  7. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
  8. . Structural Predictive Model of Presenilin-2 Protein and Analysis of Structural Effects of Familial Alzheimer's Disease Mutations. Biochem Res Int. 2021;2021:9542038. Epub 2021 Nov 29 PubMed.

Further Reading


  1. . Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet. 1996 Jul;5(7):985-8. PubMed.

Protein Diagram

Primary Papers

  1. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.

Other mutations at this position


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