Is PREP p.Thr374Ser (c.1121C>G) pathogenic?

PREP p.Thr374Ser (c.1121C>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0929); Ultra-rare (popmax 0.0334%, afr).

How common is PREP p.Thr374Ser (c.1121C>G) in the general population?

PREP p.Thr374Ser (c.1121C>G) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

What do computational predictors say about PREP p.Thr374Ser (c.1121C>G)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

PREP p.Thr374Ser

c.1121C>G · rs149545819 · VCV2562240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Overall
CADD	16.54	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 0.0334% African / African-American · 25/74,916 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.0044% 71/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,997
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00322%	31,053

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.Thr374Ser
Coding: c.1121C>G
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs149545819
Type: single nucleotide variant
Location: chr6:105328921 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 374: 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-thr374ser (accessed [today's date]).

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