# NM_000447.3(PSEN2):c.342_343del (p.Lys115fs)

https://sugi.bio/variant/psen2-p-lys115fs

## Summary

**PSEN2 p.Lys115fs (c.342_343del)** is classified **Pathogenic** in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). Very rare (popmax 0.00034%, nfe); Associated with Alzheimer disease 4.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00034%, nfe)

## For patients & families {#patients}

This is a change in the PSEN2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Alzheimer disease 4.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PSEN2 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Early-onset autosomal dominant Alzheimer disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Agitation — Very frequent (99-80%)
- Dementia — Very frequent (99-80%)
- Hallucinations — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypertonia — Very frequent (99-80%)
- Confusion — Very frequent (99-80%)
- Parkinsonism — Very frequent (99-80%)
- Myoclonus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016511/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PSEN2](https://sugi.bio/atlas/gene/PSEN2/) |
| Protein change (HGVS p.) | p.Lys115fs |
| Coding change (HGVS c.) | c.342_343del |
| MANE Select transcript | [NM_000447](https://www.ncbi.nlm.nih.gov/nuccore/NM_000447) |
| Variant type | Microsatellite |
| Location | chr1:226883902-226883903 (GRCh38) |
| ClinVar | [VCV3720283](https://www.ncbi.nlm.nih.gov/clinvar/variation/3720283/) |

**All HGVS expressions:** `LRG_225:g.18720GA[1]`, `LRG_225t1:c.342_343del`, `NC_000001.10:g.227071604GA[1]`, `NC_000001.11:g.226883903GA[1]`, `NG_007381.2:g.18720GA[1]`, `NM_000447.3:c.342_343del`, `NM_012486.3:c.342_343del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.761, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.85, pLI 3.9828e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,178,036 in the highest group · 5/1,599,752 alleles overall — very rare (popmax 0.00034%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,226 |
| European (non-Finnish) (grpmax) | 0.00034% | 294,509 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PSEN2** population constraint: LOEUF 0.85, pLI 3.9828e-07, missense-Z 1.3643. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dilated cardiomyopathy 1V** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.99, 38% of residues very-high.

**2 experimental structure(s)** (PDB): [7Y5X](https://www.rcsb.org/structure/7Y5X), [7Y5Z](https://www.rcsb.org/structure/7Y5Z).

## What this gene does {#gene-function}

*Describes the biological roles of PSEN2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PSEN2's established molecular role includes aspartic endopeptidase activity, intramembrane cleaving. In Reactome, PSEN2 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** PSEN2 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606).

### Pathways affected {#pathways}

PSEN2 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [NOTCH3 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013507) | curated |
| [NRIF signals cell death from the nucleus](https://reactome.org/content/detail/R-HSA-205043) | curated |
| [Noncanonical activation of NOTCH3](https://reactome.org/content/detail/R-HSA-9017802) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |
| [Regulated proteolysis of p75NTR](https://reactome.org/content/detail/R-HSA-193692) | curated |
| [TGFBR3 PTM regulation](https://reactome.org/content/detail/R-HSA-9839383) | curated |
| [Activated NOTCH1 Transmits Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2122948) | electronic |
| [NOTCH2 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2979096) | electronic |
| [NOTCH4 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013700) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** aspartic endopeptidase activity, intramembrane cleaving.

**Biological process:** membrane protein ectodomain proteolysis, protein processing, amyloid-beta formation, Notch receptor processing, ligand-dependent, amyloid precursor protein catabolic process, regulation of calcium import into the mitochondrion.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-27.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-27 |

## Associated conditions {#conditions}

[Alzheimer disease 4](https://sugi.bio/atlas/disease/alzheimer-disease-4/).

**Reported phenotype names (ClinVar):** Alzheimer disease 4.

## Similar variants {#similar}

Related PSEN2 variant pages (same residue, condition, or type): [PSEN2 p.Asn141Ile](/variant/psen2-p-asn141ile), [PSEN2 p.Thr122Pro](/variant/psen2-p-thr122pro), [PSEN2 c.970+3_970+6del](/variant/psen2-c-970-plus-3-970-plus-6del), [PSEN2 c.*20G>A](/variant/psen2-c-star-20g-a), [PSEN2 p.Ala258Thr](/variant/psen2-p-ala258thr), [PSEN2 p.Ala291Val](/variant/psen2-p-ala291val), [PSEN2 p.Arg110Cys](/variant/psen2-p-arg110cys), [PSEN2 p.Arg29Cys](/variant/psen2-p-arg29cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3720283). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*