Is PREPL p.Ile550Val (c.1648A>G) pathogenic?

PREPL p.Ile550Val (c.1648A>G) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.1705); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with PREPL p.Ile550Val (c.1648A>G)?

PREPL p.Ile550Val (c.1648A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PREPL p.Ile550Val (c.1648A>G) in the general population?

PREPL p.Ile550Val (c.1648A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PREPL p.Ile550Val (c.1648A>G)?

AlphaMissense predicts likely benign (score 0.1705) — an in-silico prediction, not a clinical call.

PREPL p.Ile550Val

c.1648A>G · VCV3309869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1705	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 I639V vs ClinVar I550V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,060 alleles

Overall 0.000124% 2/1,613,740 alleles · very rare exomes 2/1,461,410 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	8.48e-05%	1,179,768

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.Ile550Val
Coding: c.1648A>G
MANE Select: NM_001171613
Type: single nucleotide variant
Location: chr2:44322836 (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 639 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); a β-strand

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-ile550val (accessed [today's date]).

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