Is PREP p.Ala274Val (c.821C>T) pathogenic?

PREP p.Ala274Val (c.821C>T) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1228); Ultra-rare (popmax 0.0184%, amr).

How common is PREP p.Ala274Val (c.821C>T) in the general population?

PREP p.Ala274Val (c.821C>T) is ultra-rare (popmax 0.0184%, amr) (gnomAD).

What do computational predictors say about PREP p.Ala274Val (c.821C>T)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

PREP p.Ala274Val

c.821C>T · VCV4144105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.62	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 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 117 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0184% Admixed American · 11/59,924 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.0054% 87/1,610,544 alleles · ultra-rare exomes 81/1,458,364 · genomes 6/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0184%	5,448
East Asian	0.0111%	8,972
Remaining individualsnot grpmax-eligible	0.00802%	12,474
African / African-American	0.00801%	12,481
European (non-Finnish)	0.00493%	20,294
Finnishnot grpmax-eligible	0.00156%	63,968
South Asian	0.0011%	90,946

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.Ala274Val
Coding: c.821C>T
MANE Select: NM_002726
Type: single nucleotide variant
Location: chr6:105352974 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 17 PDB

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

Similar variants

PREP p.Ala274Thr Likely benign ★ same residue
PREP c.1839-2A>G Pathogenic ★ same type
PREP p.Ala110Ser Uncertain significance ★ ⚠ same type
PREP p.Ala145Thr 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-ala274val (accessed [today's date]).

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