Is PREPL p.Pro597= (c.1791T>C) pathogenic?

PREPL p.Pro597= (c.1791T>C) is classified Likely benign in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-21). Ultra-rare (popmax 0.0967%, amr); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Pro597= (c.1791T>C)?

PREPL p.Pro597= (c.1791T>C) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Pro597= (c.1791T>C) in the general population?

PREPL p.Pro597= (c.1791T>C) is ultra-rare (popmax 0.0967%, amr) (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.Pro597=

c.1791T>C · rs189954086 · VCV705724

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0967%, amr)

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.008	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -3, phastCons 1
Overall
CADD	8.957	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0967% Admixed American · 58/60,010 alleles

Filtering AF 0.0767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0696%

Overall 0.00421% 68/1,613,742 alleles · ultra-rare exomes 37/1,461,440 · genomes 31/152,302 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0967%	1,035
Remaining individualsnot grpmax-eligible	0.0112%	8,928
African / African-American	0.00267%	37,517
European (non-Finnish)	8.48e-05%	1,179,668

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.Pro597=
Coding: c.1791T>C
MANE Select: NM_001171613
dbSNP: rs189954086
Type: single nucleotide variant
Location: chr2:44321863 (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 597: a UniProt-annotated variant site (found in a patient with intellectual disability, short stature, chronic lung disease and failure to thrive; uncertain significance)

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.Pro597Leu Uncertain significance ★★ ⚠ same residue
PREPL c.1262+1G>A Pathogenic/Likely pathogenic ★★ same condition
PREPL c.1263-1G>C Pathogenic/Likely pathogenic ★★ same condition
PREPL c.-49+1734C>T Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Gln14Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Gln456Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Glu577Ter 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-pro597 (accessed [today's date]).

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