Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr1:227083249 A>C
dbSNP ID: rs63750110
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: GAC to GCC


This mutation was identified in a three-generation Spanish kindred from Barcelona, known as Barc1. The proband developed behavioral disturbances and progressive cognitive decline starting at age 52. He was diagnosed with probable AD. The proband's mother had AD (onset: 60 years) and his father had unspecified dementia (onset: 67 years). DNA testing in the parents was not possible, but the mutation was absent in all six of the proband's cognitively healthy relatives. It was also absent in 130 unrelated individuals (50 healthy controls and 80 AD patients) indicating it is unlikely to be a common polymorphism (Lleó et al., 2001; Lleó et al., 2002).

More recently, the D439A mutation was detected in one control individual in a study assessing 72 AD cases and 58 controls. There was no family history of AD. The age at which this person died was not reported, nor were details regarding his or her cognitive health. Notably, this D439A carrier lacked significant AD pathology in the brain (Frigerio et al., 2015).


Unknown. Imaging in the proband of the Barcelona kindred showed moderate cortical atrophy in the frontal and parietal regions (Lleó et al., 2001). No significant AD pathology was observed in another carrier of this variant (Frigerio et al., 2015).

Biological Effect

The 439 residue is located near the C-terminal of the presenilin-2 protein and it is conserved in presenilin-1. In vitro studies do not support a functional effect. When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the D439A variant did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. Similarly, when co-transfected with APP carrying the Swedish mutation, D439A-PSEN2 did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005).

In silico, PolyPhen2 predicted the D439A variant was probably damaging (Frigerio et al., 2015).


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Paper Citations

  1. . A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001 Nov 27;57(10):1926-8. PubMed.
  2. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
  3. . 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.

Other Citations

  1. Frigerio et al., 2015

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001 Nov 27;57(10):1926-8. PubMed.