Is PREPL p.Asp307Val (c.920A>T) pathogenic?

PREPL p.Asp307Val (c.920A>T) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: ambiguous (0.3672); Very rare (popmax 0.00133%, afr); Associated with myasthenic syndrome, congenital, 22.

What condition is associated with PREPL p.Asp307Val (c.920A>T)?

PREPL p.Asp307Val (c.920A>T) is associated with myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Asp307Val (c.920A>T) in the general population?

PREPL p.Asp307Val (c.920A>T) is very rare (popmax 0.00133%, 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.Asp307Val (c.920A>T)?

AlphaMissense predicts ambiguous (score 0.3672) — an in-silico prediction, not a clinical call.

PREPL p.Asp307Val

c.920A>T · rs1674235649 · VCV839579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

myasthenic syndrome, congenital, 22

Computational evidence

Protein change
AlphaMissense	0.3672	ambiguous
REVEL	0.199	benign-leaning
SaProt	LLR -6.80	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	23.8	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 D396V vs ClinVar D307V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,036 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,868 alleles · very rare exomes 7/1,461,580 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,036
European (non-Finnish)	0.000509%	196,635

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.Asp307Val
Coding: c.920A>T
MANE Select: NM_001171613
dbSNP: rs1674235649
Type: single nucleotide variant
Location: chr2:44332625 (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-asp307val (accessed [today's date]).

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