Is PSEN2 p.His87= (c.261C>T) pathogenic?

PSEN2 p.His87= (c.261C>T) is classified Benign in PSEN2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Common (popmax 65.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Alzheimer disease 4.

What condition is associated with PSEN2 p.His87= (c.261C>T)?

PSEN2 p.His87= (c.261C>T) is associated with Alzheimer disease 4, dilated cardiomyopathy 1V (ClinVar).

PSEN2 p.His87=

Q: How common is PSEN2 p.His87= (c.261C>T) in the general population?

PSEN2 p.His87= (c.261C>T) is common (popmax 65.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.261C>T · rs1046240 · VCV256181

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 65.5%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

Alzheimer disease 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.3	GERP -3.5
Overall
CADD	5.361	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 65.5% Middle Eastern · 3,971/6,058 alleles

Filtering AF 63.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.2%

Overall 51.1% 825,347/1,613,636 alleles · common exomes 751,560/1,461,712 · genomes 73,787/151,924 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	65.5%	2
Ashkenazi Jewishnot grpmax-eligible	61.7%	2
Amishnot grpmax-eligible	57.5%	2
Finnishnot grpmax-eligible	53.6%	2
European (non-Finnish)	52.4%	2
Admixed American	52.3%	2
Remaining individualsnot grpmax-eligible	51.5%	2
East Asian	43.8%	2
South Asian	41.6%	2
African / African-American	39%	3

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.His87=
Coding: c.261C>T
MANE Select: NM_000447
dbSNP: rs1046240
Type: single nucleotide variant
Location: chr1:226883824 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB
Residue 87: an α-helix

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.His87Arg Uncertain significance ★ same residue
PSEN2 p.His87Leu Uncertain significance ★ 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

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-his87 (accessed [today's date]).

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