Is PREPL p.Pro509Ala (c.1525C>G) pathogenic?

PREPL p.Pro509Ala (c.1525C>G) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: ambiguous (0.4439); Very rare (popmax 0.000341%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PREPL p.Pro509Ala (c.1525C>G)?

PREPL p.Pro509Ala (c.1525C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PREPL p.Pro509Ala (c.1525C>G) in the general population?

PREPL p.Pro509Ala (c.1525C>G) is very rare (popmax 0.000341%, nfe) (gnomAD).

What do computational predictors say about PREPL p.Pro509Ala (c.1525C>G)?

AlphaMissense predicts ambiguous (score 0.4439) — an in-silico prediction, not a clinical call.

PREPL p.Pro509Ala

c.1525C>G · rs2103696106 · VCV3218549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4439	ambiguous
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -4.72	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	28.2	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 P598A vs ClinVar P509A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000341% European (non-Finnish) · 4/1,174,016 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,606,784 alleles · very rare exomes 4/1,454,626 · genomes 0/152,158 · 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.Pro509Ala
Coding: c.1525C>G
MANE Select: NM_001171613
dbSNP: rs2103696106
Type: single nucleotide variant
Location: chr2:44323366 (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 598 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

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

Similar variants

PREPL p.Pro509= Likely benign ★ same residue
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

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-pro509ala (accessed [today's date]).

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