Is PREPL p.Phe629= (c.1887C>T) pathogenic?

PREPL p.Phe629= (c.1887C>T) is classified Likely benign in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). Ultra-rare (popmax 0.0281%, afr); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Phe629= (c.1887C>T)?

PREPL p.Phe629= (c.1887C>T) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Phe629= (c.1887C>T) in the general population?

PREPL p.Phe629= (c.1887C>T) is ultra-rare (popmax 0.0281%, 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.Phe629=

c.1887C>T · rs368734097 · VCV1582351

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, afr)

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.3	GERP -5
Overall
CADD	7.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0281% African / African-American · 21/74,768 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00285% 46/1,611,924 alleles · ultra-rare exomes 34/1,460,016 · genomes 12/151,908 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0281%	3,560
Admixed American	0.00501%	19,969
East Asian	0.00223%	44,854
European (non-Finnish)	0.0017%	58,927
Remaining individualsnot grpmax-eligible	0.0016%	62,414

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.Phe629=
Coding: c.1887C>T
MANE Select: NM_001171613
dbSNP: rs368734097
Type: single nucleotide variant
Location: chr2:44321386 (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 629: 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-phe629 (accessed [today's date]).

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