Is PREP p.Lys373Asn (c.1119G>C) pathogenic?

PREP p.Lys373Asn (c.1119G>C) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: ambiguous (0.5201); Very rare (popmax 0.00178%, nfe).

How common is PREP p.Lys373Asn (c.1119G>C) in the general population?

PREP p.Lys373Asn (c.1119G>C) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about PREP p.Lys373Asn (c.1119G>C)?

AlphaMissense predicts ambiguous (score 0.5201) — an in-silico prediction, not a clinical call.

PREP p.Lys373Asn

c.1119G>C · rs765006643 · VCV2254991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5201	ambiguous
REVEL	0.057	moderately benign-leaning
SaProt	LLR -11.47	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 117 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	20.2	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 0.00178% European (non-Finnish) · 21/1,180,036 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00143% 23/1,614,006 alleles · very rare exomes 22/1,461,886 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.00178%	56,192

Remaining individuals 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.Lys373Asn
Coding: c.1119G>C
MANE Select: NM_002726
dbSNP: rs765006643
Type: single nucleotide variant
Location: chr6:105328923 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 17 PDB
Residue 373: a β-strand

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

Similar variants

PREP c.1839-2A>G Pathogenic ★ same type
PREP p.Ala110Ser Uncertain significance ★ ⚠ same type
PREP p.Ala145Thr Uncertain significance ★ ⚠ same type
PREP p.Ala274Val Uncertain significance ★ ⚠ same type
PREP p.Ala370Thr Uncertain significance ★ ⚠ same type
PREP p.Ala678Val Uncertain significance ★ ⚠ same type
PREP p.Arg252Met Uncertain significance ★ ⚠ same type
PREP p.Arg306Cys 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-lys373asn (accessed [today's date]).

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