Is PREP p.Leu548Val (c.1642C>G) pathogenic?

PREP p.Leu548Val (c.1642C>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.2223); Very rare (popmax 0.005%, amr).

How common is PREP p.Leu548Val (c.1642C>G) in the general population?

PREP p.Leu548Val (c.1642C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PREP p.Leu548Val (c.1642C>G)?

AlphaMissense predicts likely benign (score 0.2223) — an in-silico prediction, not a clinical call.

PREP p.Leu548Val

c.1642C>G · VCV4571928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2223 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2223	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2.7, phastCons 1
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,000
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: PREP
Protein: p.Leu548Val
Coding: c.1642C>G
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105282490 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 548: an α-helix; a disulfide bond

Full PREP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ ⚠ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg32Trp Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg545Gln Uncertain significance ★★ ⚠ same type

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/prep-p-leu548val (accessed [today's date]).

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