Is PSEN2 p.Ser22= (c.66G>A) pathogenic?

PSEN2 p.Ser22= (c.66G>A) is classified Likely benign in PSEN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-16). Ultra-rare (popmax 0.0176%, sas); Associated with Alzheimer disease 4.

What condition is associated with PSEN2 p.Ser22= (c.66G>A)?

PSEN2 p.Ser22= (c.66G>A) is associated with Alzheimer disease 4 (ClinVar).

How common is PSEN2 p.Ser22= (c.66G>A) in the general population?

PSEN2 p.Ser22= (c.66G>A) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

PSEN2 p.Ser22=

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.66G>A · rs367645069 · VCV448150

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

Alzheimer disease 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3
Overall
CADD	0.074	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/91,086 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.0105% 170/1,613,944 alleles · ultra-rare exomes 145/1,461,776 · genomes 25/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,693
Finnishnot grpmax-eligible	0.0172%	5,819
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.0111%	9,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,453
Admixed American	0.00167%	59,990

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.Ser22=
Coding: c.66G>A
MANE Select: NM_000447
dbSNP: rs367645069
Type: single nucleotide variant
Location: chr1:226881973 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 22: the 'disordered' region; a modified residue (phosphoserine)

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.Ser22Leu Uncertain significance ★ ⚠ same residue
PSEN2 p.Asn141Ile Pathogenic ★★ same condition
PSEN2 p.Thr122Pro Pathogenic/Likely pathogenic ★★ 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-ser22 (accessed [today's date]).

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