Is PREPL p.Phe339fs (c.1015_1018del) pathogenic?

PREPL p.Phe339fs (c.10151018del) is classified Pathogenic in PREPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-31). Very rare (popmax 0.00223%, eas); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Phe339fs (c.1015_1018del)?

PREPL p.Phe339fs (c.1015_1018del) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Phe339fs (c.1015_1018del) in the general population?

PREPL p.Phe339fs (c.1015_1018del) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Congenital myasthenic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PREPL p.Phe339fs

c.1015_1018del · rs748639083 · VCV691883

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

myasthenic syndrome, congenital, 22

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 8 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 0.55, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,614,146 alleles · very rare exomes 4/1,461,858 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	0.000169%	590,002

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: PREPL
Protein: p.Phe339fs
Coding: c.1015_1018del
MANE Select: NM_001171613
dbSNP: rs748639083
Type: Deletion
Location: chr2:44332527 (GRCh38)
Gene constraint: LOEUF 1.247 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 2 PDB
Residue 339: a β-strand

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

Disease context

myasthenic syndrome, congenital, 22 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PREPL p.Phe339= Likely benign ★ same residue
PREPL c.-42del Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Leu56fs Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Phe31fs Pathogenic/Likely pathogenic ★★ same condition
PREPL c.1412_1479+41del Likely pathogenic ★ same condition
PREPL c.-31_-28del Pathogenic ★ same condition
PREPL p.Ala244fs Likely pathogenic ★ same condition
PREPL p.Asp124fs Pathogenic ★ 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-phe339fs (accessed [today's date]).

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