Is PREP p.Met452Val (c.1354A>G) pathogenic?

PREP p.Met452Val (c.1354A>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.213); Ultra-rare (popmax 0.0165%, mid).

How common is PREP p.Met452Val (c.1354A>G) in the general population?

PREP p.Met452Val (c.1354A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PREP p.Met452Val (c.1354A>G)?

AlphaMissense predicts likely benign (score 0.213) — an in-silico prediction, not a clinical call.

PREP p.Met452Val

c.1354A>G · rs145698846 · VCV2454736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.213	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -13.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Overall
CADD	26.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00886% 143/1,613,528 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.0117%	8,573
European (non-Finnish)	0.0101%	9,911
East Asian	0.00668%	14,961
South Asian	0.00659%	15,180
Remaining individualsnot grpmax-eligible	0.0064%	15,624
African / African-American	0.004%	25,011

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.Met452Val
Coding: c.1354A>G
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs145698846
Type: single nucleotide variant
Location: chr6:105288858 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 452: a disulfide bond; an α-helix

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

Similar variants

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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-met452val (accessed [today's date]).

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