Is PREPL p.Ser321Pro (c.961T>C) pathogenic?

PREPL p.Ser321Pro (c.961T>C) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-14). AlphaMissense: likely pathogenic (0.992); Very rare (popmax 0.000424%, nfe); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Ser321Pro (c.961T>C)?

PREPL p.Ser321Pro (c.961T>C) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Ser321Pro (c.961T>C) in the general population?

PREPL p.Ser321Pro (c.961T>C) is very rare (popmax 0.000424%, 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.Ser321Pro (c.961T>C)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

PREPL p.Ser321Pro

c.961T>C · rs1367770744 · VCV1351740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic · top 1% in PREPL
REVEL	0.683	pathogenic-leaning
SaProt	LLR -15.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 S410P vs ClinVar S321P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,836 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,782 alleles · very rare exomes 3/1,461,664 · genomes 2/152,118 · joint denominator

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.Ser321Pro
Coding: c.961T>C
MANE Select: NM_001171613
dbSNP: rs1367770744
Type: single nucleotide variant
Location: chr2:44332584 (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-ser321pro (accessed [today's date]).

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