Is PSEN2 p.Pro69Ala (c.205C>G) pathogenic?

PSEN2 p.Pro69Ala (c.205C>G) is classified Conflicting classifications of pathogenicity in PSEN2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0593); Very rare (popmax 0.00686%, nfe); Associated with Alzheimer disease 4.

What condition is associated with PSEN2 p.Pro69Ala (c.205C>G)?

PSEN2 p.Pro69Ala (c.205C>G) is associated with Alzheimer disease 4, dilated cardiomyopathy 1V (ClinVar).

How common is PSEN2 p.Pro69Ala (c.205C>G) in the general population?

PSEN2 p.Pro69Ala (c.205C>G) is very rare (popmax 0.00686%, nfe) (gnomAD).

What do computational predictors say about PSEN2 p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

PSEN2 p.Pro69Ala

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.205C>G · rs202133351 · VCV191771

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alzheimer disease 4

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.34, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 14 kb · p 0.0074 · regional, not allelic
Overall
CADD	12.81	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

Grpmax group 0.00686% European (non-Finnish) · 81/1,180,006 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00595% 96/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,112
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)grpmax	0.00686%	14,568
African / African-American	0.00134%	74,894

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro69Ala
Coding: c.205C>G
MANE Select: NM_000447
dbSNP: rs202133351
Type: single nucleotide variant
Location: chr1:226883768 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 69: the 'disordered' region

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

Also linked: dilated cardiomyopathy 1V

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

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

Similar variants

PSEN2 p.Pro69= Likely benign ★★ 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-pro69ala (accessed [today's date]).

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