Is PSEN2 p.Phe422= (c.1266C>T) pathogenic?

PSEN2 p.Phe422= (c.1266C>T) is classified Likely benign in PSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). Ultra-rare (popmax 0.0201%, eas); Associated with Alzheimer disease 4.

What condition is associated with PSEN2 p.Phe422= (c.1266C>T)?

PSEN2 p.Phe422= (c.1266C>T) is associated with Alzheimer disease 4 (ClinVar).

How common is PSEN2 p.Phe422= (c.1266C>T) in the general population?

PSEN2 p.Phe422= (c.1266C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

PSEN2 p.Phe422=

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.1266C>T · VCV3672157

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

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 -11	GERP -3.9
Overall
CADD	6.258	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,884 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00204% 33/1,613,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,987
South Asian	0.0033%	30,344
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00161%	62,105

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.Phe422=
Coding: c.1266C>T
MANE Select: NM_000447
Type: single nucleotide variant
Location: chr1:226895498 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 422: an α-helix

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.Phe422Leu 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-phe422 (accessed [today's date]).

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