Is PREP p.Ser465Cys (c.1394C>G) pathogenic?

PREP p.Ser465Cys (c.1394C>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely benign (0.1354); Very rare (popmax 0.004%, afr).

How common is PREP p.Ser465Cys (c.1394C>G) in the general population?

PREP p.Ser465Cys (c.1394C>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about PREP p.Ser465Cys (c.1394C>G)?

AlphaMissense predicts likely benign (score 0.1354) — an in-silico prediction, not a clinical call.

PREP p.Ser465Cys

c.1394C>G · rs776787804 · VCV2314309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1354	likely benign
REVEL	0.408	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.8, phastCons 1
Overall
CADD	24.7	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 0.004% African / African-American · 3/74,932 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
European (non-Finnish)	0.00127%	78,663
South Asian	0.0011%	91,086

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.Ser465Cys
Coding: c.1394C>G
MANE Select: NM_014889 · reported on NM_002726
dbSNP: rs776787804
Type: single nucleotide variant
Location: chr6:105288818 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 465: a disulfide bond; an α-helix

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

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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-ser465cys (accessed [today's date]).

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