Is PSEN2 p.Lys115fs (c.342_343del) pathogenic?

PSEN2 p.Lys115fs (c.342343del) 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.

What condition is associated with PSEN2 p.Lys115fs (c.342_343del)?

PSEN2 p.Lys115fs (c.342_343del) is associated with Alzheimer disease 4 (ClinVar).

How common is PSEN2 p.Lys115fs (c.342_343del) in the general population?

PSEN2 p.Lys115fs (c.342_343del) is very rare (popmax 0.00034%, nfe) (gnomAD).

PSEN2 p.Lys115fs

Q: How is Early-onset autosomal dominant Alzheimer disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.342_343del · VCV3720283

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Conditions

Alzheimer disease 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,178,036 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000313% 5/1,599,752 alleles · very rare exomes 5/1,460,254 · genomes 0/139,498 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot 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 above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PSEN2
Protein: p.Lys115fs
Coding: c.342_343del
MANE Select: NM_000447
Type: Microsatellite
Location: chr1:226883902 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB

Full PSEN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alzheimer disease 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early-onset autosomal dominant Alzheimer disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PSEN2 p.Asn141Ile Pathogenic ★★ same condition
PSEN2 p.Thr122Pro Pathogenic/Likely pathogenic ★★ same condition
PSEN2 c.970+3_970+6del Uncertain significance ★★ same condition
PSEN2 c.*20G>A Uncertain significance ★★ same condition
PSEN2 p.Ala258Thr Uncertain significance ★★ ⚠ same condition
PSEN2 p.Ala291Val Uncertain significance ★★ ⚠ same condition
PSEN2 p.Arg110Cys Uncertain significance ★★ ⚠ same condition
PSEN2 p.Arg29Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/psen2-p-lys115fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown