Is PREP p.Phe186Tyr (c.557T>A) pathogenic?

PREP p.Phe186Tyr (c.557T>A) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely pathogenic (0.5872); Ultra-rare (popmax 0.0103%, nfe).

How common is PREP p.Phe186Tyr (c.557T>A) in the general population?

PREP p.Phe186Tyr (c.557T>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about PREP p.Phe186Tyr (c.557T>A)?

AlphaMissense predicts likely pathogenic (score 0.5872) — an in-silico prediction, not a clinical call.

PREP p.Phe186Tyr

c.557T>A · rs369321437 · VCV2411237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5872	likely pathogenic
REVEL	0.481	indeterminate
SaProt	LLR -11.97	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 2.3, phastCons 1
Overall
CADD	29.1	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 0.0103% European (non-Finnish) · 122/1,180,050 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00818% 132/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,673
African / African-American	0.00934%	10,706
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Phe186Tyr
Coding: c.557T>A
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs369321437
Type: single nucleotide variant
Location: chr6:105373407 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 186: a disulfide bond; a β-strand

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

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PITRM1 p.Ala887Val 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-phe186tyr (accessed [today's date]).

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