Is PREP p.Tyr408Cys (c.1223A>G) pathogenic?

PREP p.Tyr408Cys (c.1223A>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.3186); Very rare (popmax 0.00533%, afr).

How common is PREP p.Tyr408Cys (c.1223A>G) in the general population?

PREP p.Tyr408Cys (c.1223A>G) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about PREP p.Tyr408Cys (c.1223A>G)?

AlphaMissense predicts likely benign (score 0.3186) — an in-silico prediction, not a clinical call.

PREP p.Tyr408Cys

c.1223A>G · VCV4144104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3186	likely benign
REVEL	0.745	pathogenic-leaning
SaProt	LLR -13.08	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.18, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 117 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	25.8	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 0.00533% African / African-American · 4/74,998 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,611,712 alleles · very rare exomes 5/1,459,376 · genomes 2/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,749
Remaining individualsnot grpmax-eligible	0.0016%	62,402
European (non-Finnish)	0.00017%	588,914

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.Tyr408Cys
Coding: c.1223A>G
MANE Select: NM_002726
Type: single nucleotide variant
Location: chr6:105323759 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 17 PDB
Residue 408: 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-tyr408cys (accessed [today's date]).

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