Is PSEN1 p.Pro267= (c.801A>G) pathogenic?

PSEN1 p.Pro267= (c.801A>G) is classified Likely benign in PSEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). Very rare (popmax 0.00223%, eas); Associated with Alzheimer disease 3.

What condition is associated with PSEN1 p.Pro267= (c.801A>G)?

PSEN1 p.Pro267= (c.801A>G) is associated with Alzheimer disease 3, Pick disease, acne inversa, familial, 3 (ClinVar).

How common is PSEN1 p.Pro267= (c.801A>G) in the general population?

PSEN1 p.Pro267= (c.801A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

PSEN1 p.Pro267=

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.801A>G · rs758814165 · VCV1631818

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Alzheimer disease 3

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 0.39	GERP 0.81, phastCons 0.65
Overall
CADD	11.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Overall 0.000124% 2/1,612,380 alleles · very rare exomes 2/1,460,092 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
Admixed American	0.00167%	60,004

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: PSEN1
Protein: p.Pro267=
Coding: c.801A>G
MANE Select: NM_000021
dbSNP: rs758814165
Type: single nucleotide variant
Location: chr14:73198062 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.27 · 27 PDB
Residue 267: a UniProt-annotated variant site (in ad3; decreased protease activity with app; increased amyloid-beta 42/amyloid-beta 40 ratio); an α-helix

Full PSEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alzheimer disease 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pick disease acne inversa, familial, 3 frontotemporal dementia

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

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

Similar variants

PSEN1 p.Pro267Leu Likely pathogenic ★★ same residue
PSEN1 p.Pro267Thr Pathogenic/Likely pathogenic ★★ same residue
PSEN1 p.Pro267Ser Likely pathogenic ★ same residue
PSEN1 p.Pro267Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
PSEN1 c.869-1G>A Pathogenic/Likely pathogenic ★★ same condition
PSEN1 p.Ala231Thr Likely pathogenic ★★ same condition
PSEN1 p.Ala246Glu Pathogenic ★★ same condition
PSEN1 p.Ala285Val Pathogenic ★★ 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/psen1-p-pro267 (accessed [today's date]).

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