Is PREPL p.Ala75= (c.225T>A) pathogenic?

PREPL p.Ala75= (c.225T>A) is classified Benign in PREPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 11.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Ala75= (c.225T>A)?

PREPL p.Ala75= (c.225T>A) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How is Congenital myasthenic syndrome inherited?

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

PREPL p.Ala75=

Q: How common is PREPL p.Ala75= (c.225T>A) in the general population?

PREPL p.Ala75= (c.225T>A) is common (popmax 11.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.225T>A · rs72875319 · VCV478318

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 11.2%, afr) — too common for a highly-penetrant pathogenic allele

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 2.7	GERP 1.4, phastCons 1
Overall
CADD	9.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.2% African / African-American · 8,373/75,002 alleles

Filtering AF 11% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.9%

Overall 0.596% 9,622/1,614,034 alleles · common exomes 4,711/1,461,774 · genomes 4,911/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.2%	9
Admixed American	0.835%	120
Remaining individualsnot grpmax-eligible	0.75%	133
Middle Eastern	0.412%	242
European (non-Finnish)	0.0203%	4,937
Finnishnot grpmax-eligible	0.0109%	9,148
South Asian	0.00878%	11,385

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.Ala75=
Coding: c.225T>A
MANE Select: NM_001171613
dbSNP: rs72875319
Type: single nucleotide variant
Location: chr2:44343869 (GRCh38)
Gene constraint: LOEUF 1.247 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 2 PDB

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-ala75 (accessed [today's date]).

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