Is PREP p.Arg85Trp (c.253C>T) pathogenic?

PREP p.Arg85Trp (c.253C>T) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.3448); Ultra-rare (popmax 0.0165%, mid).

How common is PREP p.Arg85Trp (c.253C>T) in the general population?

PREP p.Arg85Trp (c.253C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PREP p.Arg85Trp (c.253C>T)?

AlphaMissense predicts ambiguous (score 0.3448) — an in-silico prediction, not a clinical call.

PREP p.Arg85Trp

c.253C>T · rs1474917244 · VCV2545636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3448 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
AlphaMissense	0.3448	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -11.07	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.5, phastCons 1
Overall
CADD	27.9	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 · 1/6,058 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000918%

Overall 0.00119% 19/1,600,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.00645%	15,515
South Asian	0.00456%	21,920
Admixed American	0.00179%	56,004
African / African-American	0.00135%	74,198
European (non-Finnish)	0.00068%	147,003

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.Arg85Trp
Coding: c.253C>T
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs1474917244
Type: single nucleotide variant
Location: chr6:105377387 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 85: a β-strand

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

Similar variants

PITRM1 p.Asn85= Likely benign ★ 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-arg85trp (accessed [today's date]).

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