Is PSENEN p.Phe25= (c.75C>T) pathogenic?

PSENEN p.Phe25= (c.75C>T) is classified Likely benign in PSENEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). Very rare (popmax 0.0011%, nfe).

How common is PSENEN p.Phe25= (c.75C>T) in the general population?

PSENEN p.Phe25= (c.75C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

PSENEN p.Phe25=

c.75C>T · VCV4708870

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

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 -0.95, phastCons 1
Overall
CADD	12.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,926 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,560 alleles · very rare

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: PSENEN
Protein: p.Phe25=
Coding: c.75C>T
MANE Select: NM_172341
Type: single nucleotide variant
Location: chr19:35746432 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 92.84 · 27 PDB
Residue 25: a turn

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

Similar variants

PSENEN p.Phe25Leu Uncertain significance ★ ⚠ same residue
PSENEN p.Ala46Asp Uncertain significance ★★ ⚠ same type
PSENEN p.Arg82Gln Uncertain significance ★★ ⚠ same type
PSENEN p.Arg84His Uncertain significance ★★ ⚠ same type
PSENEN p.Gly86Cys Uncertain significance ★★ ⚠ same type
PSENEN p.Leu43Phe Uncertain significance ★★ ⚠ same type
PSENEN p.Pro45Ser Uncertain significance ★★ ⚠ same type
PSENEN p.Thr100Asn Uncertain significance ★★ ⚠ same type

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/psenen-p-phe25 (accessed [today's date]).

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