Is PREP p.Val293Ala (c.878T>C) pathogenic?

PREP p.Val293Ala (c.878T>C) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.5946); Very rare (popmax 0.00127%, nfe).

How common is PREP p.Val293Ala (c.878T>C) in the general population?

PREP p.Val293Ala (c.878T>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about PREP p.Val293Ala (c.878T>C)?

AlphaMissense predicts likely pathogenic (score 0.5946) — an in-silico prediction, not a clinical call.

PREP p.Val293Ala

c.878T>C · VCV3783156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5946	likely pathogenic
REVEL	0.399	indeterminate
SaProt	LLR -11.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Overall
CADD	27.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,036 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)grpmax	0.00127%	78,669

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val293Ala
Coding: c.878T>C
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105333451 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 293: a disulfide bond

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

Similar variants

PREP p.Val293Leu Uncertain significance ★ ⚠ same residue
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

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-val293ala (accessed [today's date]).

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