Is PSEN2 p.Pro318= (c.954C>T) pathogenic?

PSEN2 p.Pro318= (c.954C>T) is classified Conflicting classifications of pathogenicity in PSEN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-17). Rare (popmax 0.149%, mid); Associated with dilated cardiomyopathy 1V.

What condition is associated with PSEN2 p.Pro318= (c.954C>T)?

PSEN2 p.Pro318= (c.954C>T) is associated with dilated cardiomyopathy 1V, Alzheimer disease 4 (ClinVar).

How common is PSEN2 p.Pro318= (c.954C>T) in the general population?

PSEN2 p.Pro318= (c.954C>T) is rare (popmax 0.149%, mid) (gnomAD).

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.Pro318=

c.954C>T · rs199587016 · VCV295994

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

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 1.4	GERP -0.8, phastCons 1
Overall
CADD	10.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.149% Middle Eastern · 9/6,060 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.0225% 363/1,613,320 alleles · rare exomes 331/1,461,012 · genomes 32/152,308 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.777%	129
Middle Easterngrpmax	0.149%	673
Remaining individualsnot grpmax-eligible	0.064%	1,561
South Asian	0.00771%	12,968
European (non-Finnish)	0.00619%	16,161
Admixed American	0.005%	19,985
African / African-American	0.00133%	75,048

Ashkenazi Jewish 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.Pro318=
Coding: c.954C>T
MANE Select: NM_000447
dbSNP: rs199587016
Type: single nucleotide variant
Location: chr1:226891345 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.99 · 2 PDB

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-pro318 (accessed [today's date]).

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