Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076680 G>A
dbSNP ID: rs63749884
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ATA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8


M239I was the third missense mutation in PSEN2 to be associated with Alzheimer's disease. Reported first in an Italian family in 2000 (Finckh et al., 2000), it has since been identified in two additional Italian families, a Brazilian family of European ancestry, and a Chinese individual. Disease in these families is quite variable, with diverse clinical presentations, including posterior cortical atrophy in one case.

The first reported kindred contains four affected members across two generations. Genetic analysis was completed in six siblings. All three affected siblings were found to carry the M139I mutation, and two of the three unaffected siblings were also found to be carriers, symptom-free at ages 58 and 68. This apparent lack of segregation may be spurious and attributable to the wide age of onset in this family, or a possible reduced penetrance of the mutation. In this family, the disease phenotype was quite variable. Onset age varied from 44 to 58 years, and likely later. Reported clinical features included seizures, myoclonic jerks, severe rigidity in the arms and legs, global cognitive deficits, and impairments in language and attention (Finckh et al., 2000).

The second Italian family included six affected individuals over two generations. The proband experienced symptom onset, notably memory impairment and a dysexecutive syndrome, at age 50. Apathy, decreased speech production, and social withdrawal were also early features. Extrapyramidal signs occurred later, including myoclonic jerks. She met NINCDS-ADRDA criteria for probable Alzheimer’s disease (McKhann et al., 1984). Four previously deceased family members had experienced onset between the ages of 45 and 50, with death following six to 11 years later. The M239I mutation was detected in the proband, but segregation with disease could not be assessed. No mutations were detected in any of the other genes screened: APP (exons 16-17), MAPT (exons, 1, 9-13), PSEN1, and PGRN. The mutation was absent in 492 unrelated individuals (Testi et al., 2012).

In a third Italian family, the M239I mutation was associated with symptoms consistent with posterior cortical atrophy. The proband was a 52-year-old man with a two-year history of depression, concentration difficulties, and severe visuospatial deficits, including the loss of the ability to a read a clock. He also had progressive deficits in writing and performing simple calculations. He had a family history of early onset dementia, with at least four additional family members affected over three generations. The family pedigree was also affected by major psychiatric disorders with psychotic features. None of the proband’s six siblings were affected by dementia symptoms at ages 42 to 64. It is unknown if they are carriers of the M239I, as they declined genetic testing. The proband was negative for mutations in PSEN1, APP (exons 16-17), PGRN, C9ORF72, and MAPT (exons 9-13) (Tremolizzo et al., 2014).

The variant was also reported in AD patients from Brazil and China. The Brazilian family was of Western European ancestry with ages at onset ranging between 49 and 51 years, and the most prominent symptoms were memory loss and behavioral changes (Llibre-Guerra et al., 2020). The Chinese patient, who also suffered from memory loss and behavioral changes, was from a large cohort study in Southern China in which 14 genes associated with neurodegenerative dementias were sequenced (Jiao et al., 2021). Her age at onset was 50 years and her APOE genotype was APOE E3/E4. She had a family history of AD. 

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


Autopsy of one individual in the first kindred identified confirmed the clinical diagnosis of AD.  Diffuse moderate cortical atrophy was observed without lacunar or large infarcts. Numerous neurofibrillary tangles and senile plaques were observed, the latter most concentrated in the amygdala and less frequent in the hippocampus (Finckh et al., 2000). MRI in the patient with posterior cortical atrophy showed atrophy in the parieto-temporo-occipital regions. FDG-PET showed significant bilateral parietal hypometabolism with milder right frontotemporal hypometabolism (Tremolizzo et al., 2014).

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the M239I 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 bearing the Swedish mutation, the M239I 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). The M239I mutation also was found to alter intracellular calcium homeostasis; specifically, it reduced calcium release in human fibroblasts and cell lines stably or transiently expressing the mutation (Zatti et al., 2004; Zatti et al., 2006).

This variant'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. M239I: 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. M239I: 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. M239I: One unaffected carrier with age above family's age at onset (AAO) range, but disease phenotype was variable, including a broad AAO range.


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.

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


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000 May 23;54(10):2006-8. PubMed.
  2. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  3. . Autosomal Dominant Alzheimer's Disease with Early Frontal Lobe Involvement Associated with the Met239Ile Mutation of Presenilin 2 Gene. J Alzheimers Dis. 2012 Jan 1;31(1):7-11. PubMed.
  4. . First Report of PSEN2 Mutation Presenting as Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2014 Jul 9; PubMed.
  5. . Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 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.
  9. . The presenilin 2 M239I mutation associated with familial Alzheimer's disease reduces Ca2+ release from intracellular stores. Neurobiol Dis. 2004 Mar;15(2):269-78. PubMed.
  10. . Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium. 2006 Jun;39(6):539-50. PubMed.

Other Citations

  1. Swedish

Further Reading

Protein Diagram

Primary Papers

  1. . Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000 May 23;54(10):2006-8. PubMed.

Other mutations at this position


Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.