Is PREPL p.Pro495Ser (c.1483C>T) pathogenic?

PREPL p.Pro495Ser (c.1483C>T) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely pathogenic (0.8995); Very rare (popmax 0.00695%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PREPL p.Pro495Ser (c.1483C>T)?

PREPL p.Pro495Ser (c.1483C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PREPL p.Pro495Ser (c.1483C>T) in the general population?

PREPL p.Pro495Ser (c.1483C>T) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about PREPL p.Pro495Ser (c.1483C>T)?

AlphaMissense predicts likely pathogenic (score 0.8995) — an in-silico prediction, not a clinical call.

PREPL p.Pro495Ser

c.1483C>T · rs757659663 · VCV2511444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8995	likely pathogenic · top 8% in PREPL
REVEL	0.727	pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, 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 P584S vs ClinVar P495S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00695% European (non-Finnish) · 81/1,165,248 alleles

Filtering AF 0.0057% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00521%

Overall 0.00533% 84/1,575,988 alleles · very rare exomes 83/1,424,058 · genomes 1/151,930 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,386
Remaining individualsnot grpmax-eligible	0.00493%	20,268

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.Pro495Ser
Coding: c.1483C>T
MANE Select: NM_001171613
dbSNP: rs757659663
Type: single nucleotide variant
Location: chr2:44323408 (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 584 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 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-pro495ser (accessed [today's date]).

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