Is PREPL p.Ala552= (c.1656A>G) pathogenic?

PREPL p.Ala552= (c.1656A>G) is classified Benign in PREPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.68%, afr); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Ala552= (c.1656A>G)?

PREPL p.Ala552= (c.1656A>G) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Ala552= (c.1656A>G) in the general population?

PREPL p.Ala552= (c.1656A>G) is low-frequency (popmax 1.68%, afr) (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.Ala552=

c.1656A>G · rs74395208 · VCV478313

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.68%, afr)

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.392	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -4.5
Overall
CADD	0.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.68% African / African-American · 1,263/75,006 alleles

Filtering AF 1.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.58%

Overall 0.173% 2,795/1,613,690 alleles · low-frequency exomes 1,908/1,461,366 · genomes 887/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.68%	59
Middle Eastern	0.792%	126
Ashkenazi Jewishnot grpmax-eligible	0.646%	155
Admixed American	0.48%	208
Remaining individualsnot grpmax-eligible	0.386%	259
European (non-Finnish)	0.0602%	1,662
South Asian	0.0571%	1,751
East Asian	0.00446%	22,437

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.Ala552=
Coding: c.1656A>G
MANE Select: NM_001171613
dbSNP: rs74395208
Type: single nucleotide variant
Location: chr2:44322828 (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 552: an α-helix; 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 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
PREPL c.1629+30C>T Uncertain significance ★★ 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-ala552 (accessed [today's date]).

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