Is PREPL p.Ala239Val (c.716C>T) pathogenic?

PREPL p.Ala239Val (c.716C>T) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-18). AlphaMissense: likely benign (0.134); Very rare (popmax 0.00288%, nfe); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Ala239Val (c.716C>T)?

PREPL p.Ala239Val (c.716C>T) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Ala239Val (c.716C>T) in the general population?

PREPL p.Ala239Val (c.716C>T) is very rare (popmax 0.00288%, nfe) (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.Ala239Val (c.716C>T)?

AlphaMissense predicts likely benign (score 0.134) — an in-silico prediction, not a clinical call.

PREPL p.Ala239Val

c.716C>T · rs778761279 · VCV950901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
AlphaMissense	0.134	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 10	GERP 2.5, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A328V vs ClinVar A239V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00288% European (non-Finnish) · 34/1,178,520 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00236% 38/1,607,600 alleles · very rare exomes 33/1,455,492 · genomes 5/152,108 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00482%	20,763
European (non-Finnish)grpmax	0.00288%	34,662
South Asian	0.00111%	89,882

Remaining individuals 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.Ala239Val
Coding: c.716C>T
MANE Select: NM_001171613
dbSNP: rs778761279
Type: single nucleotide variant
Location: chr2:44338523 (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 328 UniProt numbering: 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.Ala239= Likely benign ★ 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-ala239val (accessed [today's date]).

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