Is PREPL p.Ile548Val (c.1642A>G) pathogenic?

PREPL p.Ile548Val (c.1642A>G) is classified Conflicting classifications of pathogenicity in PREPL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-04). AlphaMissense: likely benign (0.0798); Ultra-rare (popmax 0.016%, afr); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Ile548Val (c.1642A>G)?

PREPL p.Ile548Val (c.1642A>G) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Ile548Val (c.1642A>G) in the general population?

PREPL p.Ile548Val (c.1642A>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

How is Congenital myasthenic syndrome inherited?

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

What do computational predictors say about PREPL p.Ile548Val (c.1642A>G)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

PREPL p.Ile548Val

c.1642A>G · rs151116193 · VCV544535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.6	GERP -4.5
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I637V vs ClinVar I548V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/75,018 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00235% 38/1,613,672 alleles · ultra-rare exomes 32/1,461,352 · genomes 6/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,251
Admixed American	0.01%	9,993
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.0022%	45,532
European (non-Finnish)	0.00127%	78,646

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.Ile548Val
Coding: c.1642A>G
MANE Select: NM_001171613
dbSNP: rs151116193
Type: single nucleotide variant
Location: chr2:44322842 (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 637 UniProt numbering: a UniProt-annotated variant site (found in a patient with intellectual disability, short stature, chronic lung disease and failure to thrive; uncertain significance); 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 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-ile548val (accessed [today's date]).

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