Is PSEN2 p.Thr44= (c.132T>A) pathogenic?

PSEN2 p.Thr44= (c.132T>A) is classified Benign/Likely benign in PSEN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). Low-frequency (popmax 1.41%, afr); Associated with Alzheimer disease 4.

What condition is associated with PSEN2 p.Thr44= (c.132T>A)?

PSEN2 p.Thr44= (c.132T>A) is associated with Alzheimer disease 4, dilated cardiomyopathy 1V (ClinVar).

How common is PSEN2 p.Thr44= (c.132T>A) in the general population?

PSEN2 p.Thr44= (c.132T>A) is low-frequency (popmax 1.41%, afr) (gnomAD).

PSEN2 p.Thr44=

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.132T>A · rs143227762 · VCV533780

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.41%, afr)

Conditions

Alzheimer disease 4

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 -8.7	GERP -3
Overall
CADD	0.222	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.41% African / African-American · 1,056/75,058 alleles

Filtering AF 1.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.31%

Overall 0.0692% 1,117/1,613,968 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.41%	71
Remaining individualsnot grpmax-eligible	0.064%	1,562
Middle Eastern	0.0498%	2,009
Admixed American	0.0267%	3,752
European (non-Finnish)	0.000169%	590,016

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.Thr44=
Coding: c.132T>A
MANE Select: NM_000447
dbSNP: rs143227762
Type: single nucleotide variant
Location: chr1:226882039 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 44: 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.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-thr44 (accessed [today's date]).

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