Is PSEN1 p.Pro88= (c.264T>C) pathogenic?

PSEN1 p.Pro88= (c.264T>C) is classified Likely benign in PSEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). Ultra-rare (popmax 0.0156%, eas); Associated with frontotemporal dementia.

What condition is associated with PSEN1 p.Pro88= (c.264T>C)?

PSEN1 p.Pro88= (c.264T>C) is associated with frontotemporal dementia, Pick disease, Alzheimer disease 3 (ClinVar).

How common is PSEN1 p.Pro88= (c.264T>C) in the general population?

PSEN1 p.Pro88= (c.264T>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

PSEN1 p.Pro88=

c.264T>C · rs201113902 · VCV1140026

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

frontotemporal dementia

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 -14	GERP -3.8
Overall
CADD	0.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,882 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000434% 7/1,614,250 alleles · ultra-rare exomes 5/1,461,872 · genomes 2/152,378 · joint denominator

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.Pro88=
Coding: c.264T>C
MANE Select: NM_000021
dbSNP: rs201113902
Type: single nucleotide variant
Location: chr14:73170973 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.27 · 27 PDB
Residue 88: an α-helix

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

Disease context

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pick disease Alzheimer disease 3 acne inversa, familial, 3

Similar variants

PSEN1 p.Pro88Arg Pathogenic ★ same residue
PSEN1 p.Pro88His Likely pathogenic ★ same residue
PSEN1 p.Pro88Thr Uncertain significance ★ ⚠ same residue
PSEN1 p.Pro88Leu 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

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-pro88 (accessed [today's date]).

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