Mutations
PSEN1 L232F
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192789 C>T
Position: (GRCh37/hg19):Chr14:73659497 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CTC to TTC
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 7
Findings
This variant was identified in a 59-year-old Dutch patient diagnosed with early onset Alzheimer’s disease (Küçükali et al., 2022). The patient was part of the EMIF-AD MBD study, a European multicenter cohort including individuals with AD and mild cognitive impairment (MCI).
This variant was absent from the gnomAD variant database (v2.1.1, Jan 2023).
Neuropathology
Neuropathological data are unavailable, but cerebrospinal fluid biomarkers were consistent with AD (Küçükali et al., 2022).
Biological Effect
In a cell-based assay, this variant increased the Aβ42/Aβ40 ratio, with a modest increase in Aβ42 levels and a decrease in Aβ40 levels (Marsh et al., 2025).
This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 26.1, suggesting a deleterious effect (Küçükali et al., 2022).
Pathogenicity
Alzheimer's Disease : Not Classified*
*Carriers of this variant are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025). This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PS3-S
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM1-M
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2-M
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.
PP2-P
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP3-P
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: 24 Mar 2025
References
Paper Citations
- Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2023 Jun;19(6):2317-2331. Epub 2022 Dec 4 PubMed.
- Marsh JA, Huang G, Bowling K, Renton AE, Ziegemeier E, Ball T, Pottier C, Cruchaga C, Day GS, Bateman RJ, Llibre-Guerra JJ, McDade E, Karch CM. Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics. 2025 Jan 27;:e00527. Epub 2025 Jan 27 PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2023 Jun;19(6):2317-2331. Epub 2022 Dec 4 PubMed.
Other mutations at this position
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