Is PREP p.Asn525fs (c.1570_1573dup) pathogenic?

PREP p.Asn525fs (c.15701573dup) is classified Pathogenic in PREP (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.000339%, nfe).

How common is PREP p.Asn525fs (c.1570_1573dup) in the general population?

PREP p.Asn525fs (c.1570_1573dup) is very rare (popmax 0.000339%, nfe) (gnomAD).

PREP p.Asn525fs

c.1570_1573dup · VCV4537358

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,972 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,754 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: PREP
Protein: p.Asn525fs
Coding: c.1570_1573dup
MANE Select: NM_014889 · reported on NM_002726
Type: Microsatellite
Location: chr6:105282558 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 525: an α-helix; a disulfide bond

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

Similar variants

PITRM1 c.267-9_267-8insCGTCCCTAGCGTGCCATTCCTCTCT Uncertain significance ★ same type
PITRM1 p.Cys241fs Uncertain significance ★ same type
PITRM1 c.791+12_791+14del Benign ★ 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/prep-p-asn525fs (accessed [today's date]).

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