Is PREP p.Pro229Thr (c.685C>A) pathogenic?

PREP p.Pro229Thr (c.685C>A) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1651); Ultra-rare (popmax 0.0158%, nfe).

How common is PREP p.Pro229Thr (c.685C>A) in the general population?

PREP p.Pro229Thr (c.685C>A) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about PREP p.Pro229Thr (c.685C>A)?

AlphaMissense predicts likely benign (score 0.1651) — an in-silico prediction, not a clinical call.

PREP p.Pro229Thr

c.685C>A · rs202011848 · VCV2409339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1651 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1651	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Overall
CADD	27.8	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 0.0158% European (non-Finnish) · 186/1,179,978 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.0129% 208/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0312%	3,201
European (non-Finnish)grpmax	0.0158%	6,344
Remaining individualsnot grpmax-eligible	0.0032%	31,236

Finnish 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.Pro229Thr
Coding: c.685C>A
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs202011848
Type: single nucleotide variant
Location: chr6:105368935 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 229: a disulfide bond

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
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr 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-pro229thr (accessed [today's date]).

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