Is PREP p.Arg312Cys (c.934C>T) pathogenic?

PREP p.Arg312Cys (c.934C>T) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.1796); Ultra-rare (popmax 0.0296%, sas).

How common is PREP p.Arg312Cys (c.934C>T) in the general population?

PREP p.Arg312Cys (c.934C>T) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about PREP p.Arg312Cys (c.934C>T)?

AlphaMissense predicts likely benign (score 0.1796) — an in-silico prediction, not a clinical call.

PREP p.Arg312Cys

c.934C>T · VCV3783152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1796	likely benign
REVEL	0.445	indeterminate
SaProt	LLR -12.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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	27.4	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 0.0296% South Asian · 27/91,082 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00378% 61/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
African / African-American	0.016%	6,242
Remaining individualsnot grpmax-eligible	0.0064%	15,622
East Asian	0.00223%	44,882
Finnishnot grpmax-eligible	0.00156%	64,034
European (non-Finnish)	0.00136%	73,751

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.Arg312Cys
Coding: c.934C>T
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.Arg312Gly 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-arg312cys (accessed [today's date]).

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