Is PREPL p.Leu475Pro (c.1424T>C) pathogenic?

PREPL p.Leu475Pro (c.1424T>C) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: ambiguous (0.3998); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PREPL p.Leu475Pro (c.1424T>C)?

PREPL p.Leu475Pro (c.1424T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PREPL p.Leu475Pro (c.1424T>C) in the general population?

PREPL p.Leu475Pro (c.1424T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PREPL p.Leu475Pro (c.1424T>C)?

AlphaMissense predicts ambiguous (score 0.3998) — an in-silico prediction, not a clinical call.

PREPL p.Leu475Pro

c.1424T>C · VCV3424835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3998	ambiguous
REVEL	0.445	indeterminate
SaProt	LLR -9.61	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	29.1	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 L564P vs ClinVar L475P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PREPL
Protein: p.Leu475Pro
Coding: c.1424T>C
MANE Select: NM_001171613
Type: single nucleotide variant
Location: chr2:44326767 (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 564 UniProt numbering: an α-helix; 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PREPL c.-29A>G Uncertain significance ★★ ⚠ same condition
PREPL c.-49+1840C>T Uncertain significance ★★ ⚠ same condition
PREPL p.Ala3Thr Uncertain significance ★★ ⚠ same condition
PREPL p.Ala432Thr Uncertain significance ★★ ⚠ same condition
PREPL p.Arg174Leu Uncertain significance ★★ ⚠ same condition
PREPL p.Arg353His Uncertain significance ★★ ⚠ same condition
PREPL p.Asn152Ser Uncertain significance ★★ ⚠ same condition
PREPL p.Asp102Asn 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-leu475pro (accessed [today's date]).

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