Is PREP p.Val427Ile (c.1279G>A) pathogenic?

PREP p.Val427Ile (c.1279G>A) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: likely benign (0.1124); Ultra-rare (popmax 0.0317%, amr).

How common is PREP p.Val427Ile (c.1279G>A) in the general population?

PREP p.Val427Ile (c.1279G>A) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about PREP p.Val427Ile (c.1279G>A)?

AlphaMissense predicts likely benign (score 0.1124) — an in-silico prediction, not a clinical call.

PREP p.Val427Ile

c.1279G>A · VCV3783151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1124	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.8, phastCons 1
Overall
CADD	20.5	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/60,004 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00657% 106/1,613,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
African / African-American	0.00801%	12,486
European (non-Finnish)	0.00644%	15,516
Remaining individualsnot grpmax-eligible	0.0048%	20,825
South Asian	0.0022%	45,537

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.Val427Ile
Coding: c.1279G>A
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105323703 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 427: 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
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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-val427ile (accessed [today's date]).

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