Is PREP p.Arg312Gly (c.934C>G) pathogenic?

PREP p.Arg312Gly (c.934C>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.5034); Very rare (popmax 0.00666%, amr).

How common is PREP p.Arg312Gly (c.934C>G) in the general population?

PREP p.Arg312Gly (c.934C>G) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about PREP p.Arg312Gly (c.934C>G)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

PREP p.Arg312Gly

c.934C>G · VCV3783159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.574	indeterminate
SaProt	LLR -11.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.4, phastCons 1
Overall
CADD	28.5	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 0.00666% Admixed American · 4/60,026 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00041% 6/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,078

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.Arg312Gly
Coding: c.934C>G
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105333395 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 312: a disulfide bond; a β-strand

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

Similar variants

PITRM1 p.Thr312= Conflicting classifications of pathogenicity ★ same residue
PREP p.Arg312Cys Uncertain significance ★ ⚠ same residue
PREP p.Arg312His 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

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-arg312gly (accessed [today's date]).

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