Is PSEN1 p.Pro433Ser (c.1297C>T) pathogenic?

PSEN1 p.Pro433Ser (c.1297C>T) is classified Likely pathogenic in PSEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-02-01). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with Alzheimer disease.

What condition is associated with PSEN1 p.Pro433Ser (c.1297C>T)?

PSEN1 p.Pro433Ser (c.1297C>T) is associated with Alzheimer disease (ClinVar).

How common is PSEN1 p.Pro433Ser (c.1297C>T) in the general population?

PSEN1 p.Pro433Ser (c.1297C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSEN1 p.Pro433Ser (c.1297C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

PSEN1 p.Pro433Ser

c.1297C>T · rs1566657804 · VCV599625

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 2% in PSEN1
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 7,345 bp · p 1.5e-09 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PSEN1
Protein: p.Pro433Ser
Coding: c.1297C>T
MANE Select: NM_000021
dbSNP: rs1566657804
Type: single nucleotide variant
Location: chr14:73219182 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.27 · 27 PDB
Residue 433: the 'required for interaction with ctnnb1' region; the 'important for cleavage of target proteins' region; a β-strand

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

Disease context

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

Similar variants

PSEN1 c.869-1G>A Pathogenic/Likely pathogenic ★★ same condition
PSEN1 p.Glu318Gly Benign/Likely benign ★★ same condition
PSEN1 p.Gln222Pro Likely pathogenic ★ same condition
PSEN1 p.Phe105Ser Likely pathogenic ★ ⚠ same condition
PSEN1 p.Val393Phe Likely pathogenic ★ same condition
PSEN1 p.Arg35Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
PSEN1 p.Val142Ile Conflicting classifications of pathogenicity ★ ⚠ same condition
PSEN1 p.Val261Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro433ser (accessed [today's date]).

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