Is PSEN2 p.Ala23= (c.69T>C) pathogenic?

PSEN2 p.Ala23= (c.69T>C) is classified Benign in PSEN2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Common (popmax 82.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with dilated cardiomyopathy 1V.

What condition is associated with PSEN2 p.Ala23= (c.69T>C)?

PSEN2 p.Ala23= (c.69T>C) is associated with dilated cardiomyopathy 1V, Alzheimer disease 4 (ClinVar).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PSEN2 p.Ala23=

Q: How common is PSEN2 p.Ala23= (c.69T>C) in the general population?

PSEN2 p.Ala23= (c.69T>C) is common (popmax 82.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.69T>C · rs11405 · VCV256184

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 82.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

dilated cardiomyopathy 1V

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 -20	GERP -3
Overall
CADD	0.028	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 82.1% African / African-American · 61,570/75,002 alleles

Filtering AF 81.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.3%

Overall 77% 1,242,351/1,613,976 alleles · common exomes 1,124,751/1,461,822 · genomes 117,600/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	82.1%	1
Middle Eastern	82%	1
Finnishnot grpmax-eligible	78.5%	1
European (non-Finnish)	77.4%	1
Ashkenazi Jewishnot grpmax-eligible	76.6%	1
Remaining individualsnot grpmax-eligible	76.5%	1
South Asian	75.4%	1
Amishnot grpmax-eligible	74.6%	1
Admixed American	74.2%	1
East Asian	62.1%	2

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.Ala23=
Coding: c.69T>C
MANE Select: NM_000447
dbSNP: rs11405
Type: single nucleotide variant
Location: chr1:226881976 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 23: the 'disordered' region

Full PSEN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dilated cardiomyopathy 1V — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease 4

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
PSEN2 p.Arg435Gln 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-ala23 (accessed [today's date]).

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