Is PREPL p.Met181fs (c.539_540dup) pathogenic?

PREPL p.Met181fs (c.539540dup) is classified Likely pathogenic in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-02). No gnomAD frequency available for this variant; Associated with PREPL-related disorder.

What condition is associated with PREPL p.Met181fs (c.539_540dup)?

PREPL p.Met181fs (c.539_540dup) is associated with PREPL-related disorder (ClinVar).

How common is PREPL p.Met181fs (c.539_540dup) in the general population?

PREPL p.Met181fs (c.539_540dup) is no gnomAD frequency available for this variant (gnomAD).

PREPL p.Met181fs

c.539_540dup · rs1057523690 · VCV2635506

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

PREPL-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PREPL
Protein: p.Met181fs
Coding: c.539_540dup
MANE Select: NM_001171613
dbSNP: rs1057523690
Type: Duplication
Location: chr2:44339308 (GRCh38)
Gene constraint: LOEUF 1.247 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 2 PDB

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

Disease context

PREPL-related disorder

Similar variants

PREPL p.Gln14Ter Pathogenic/Likely pathogenic ★★ same condition
SLC3A1 p.Arg567fs Pathogenic ★★ same condition
PREPL p.Tyr53Ter Likely pathogenic ★ same condition
PREPL p.Gly391Glu Uncertain significance ⚠ same condition
PREPL c.1480-5T>C Likely benign same condition
PREPL c.1827+4T>C Likely benign same condition
PREPL c.-49+1660A>G Likely benign same condition
PREPL p.Arg293= Likely benign 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/prepl-p-met181fs (accessed [today's date]).

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