Is PSEN1 p.Pro264= (c.792G>A) pathogenic?

PSEN1 p.Pro264= (c.792G>A) is classified Likely benign in PSEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). Ultra-rare (popmax 0.0494%, afr); Associated with Alzheimer disease 3.

What condition is associated with PSEN1 p.Pro264= (c.792G>A)?

PSEN1 p.Pro264= (c.792G>A) is associated with Alzheimer disease 3, Pick disease, acne inversa, familial, 3 (ClinVar).

How common is PSEN1 p.Pro264= (c.792G>A) in the general population?

PSEN1 p.Pro264= (c.792G>A) is ultra-rare (popmax 0.0494%, afr) (gnomAD).

PSEN1 p.Pro264=

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.792G>A · rs150301281 · VCV1962493

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, afr)

Conditions

Alzheimer disease 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.4	GERP -3.5, phastCons 0.001
Overall
CADD	12.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% African / African-American · 37/74,826 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00354% 57/1,610,342 alleles · ultra-rare exomes 34/1,458,276 · genomes 23/152,066 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0494%	2,022
Admixed American	0.00667%	14,990
Remaining individualsnot grpmax-eligible	0.00321%	31,181
South Asian	0.0022%	45,454
European (non-Finnish)	0.00102%	98,093

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.Pro264=
Coding: c.792G>A
MANE Select: NM_000021
dbSNP: rs150301281
Type: single nucleotide variant
Location: chr14:73198053 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.27 · 27 PDB
Residue 264: a UniProt-annotated variant site (in ad3; decreased protease activity with app; increased amyloid-beta 42/amyloid-beta 40 ratio; impaired ability to cleave ephb2/ctf1); a β-strand

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.Pro264Leu Pathogenic/Likely pathogenic ★★ 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
PSEN1 p.Ala426Pro Pathogenic/Likely pathogenic ★★ same condition
PSEN1 p.Ala431Glu Pathogenic ★★ same condition
PSEN1 p.Ala79Val 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-pro264 (accessed [today's date]).

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