Is PREPL p.Arg421Gln (c.1262G>A) pathogenic?

PREPL p.Arg421Gln (c.1262G>A) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-01). AlphaMissense: likely pathogenic (0.6971); Ultra-rare (popmax 0.0166%, mid); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Arg421Gln (c.1262G>A)?

PREPL p.Arg421Gln (c.1262G>A) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Arg421Gln (c.1262G>A) in the general population?

PREPL p.Arg421Gln (c.1262G>A) is ultra-rare (popmax 0.0166%, mid) (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.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely pathogenic (score 0.6971) — an in-silico prediction, not a clinical call.

PREPL p.Arg421Gln

c.1262G>A · rs754572953 · VCV650135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6971 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
AlphaMissense	0.6971	likely pathogenic
REVEL	0.521	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.34	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.28 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	35.0	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 R510Q vs ClinVar R421Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,032 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00242% 39/1,609,218 alleles · ultra-rare exomes 36/1,456,990 · genomes 3/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,032
East Asian	0.0111%	8,971
Remaining individualsnot grpmax-eligible	0.00481%	20,771
European (non-Finnish)	0.00246%	40,628
South Asian	0.00111%	89,752

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_001171613
dbSNP: rs754572953
Type: single nucleotide variant
Location: chr2:44328937 (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 510 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)

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.Arg421Ter Pathogenic ★ 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-arg421gln (accessed [today's date]).

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