Is PREP p.Ala274Thr (c.820G>A) pathogenic?

PREP p.Ala274Thr (c.820G>A) is classified Likely benign in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.0608); Ultra-rare (popmax 0.0134%, eas).

How common is PREP p.Ala274Thr (c.820G>A) in the general population?

PREP p.Ala274Thr (c.820G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about PREP p.Ala274Thr (c.820G>A)?

AlphaMissense predicts likely benign (score 0.0608) — an in-silico prediction, not a clinical call.

PREP p.Ala274Thr

c.820G>A · VCV4144107

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0608 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0608	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -2.06	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 2.9	GERP 1.3, phastCons 1
Overall
CADD	14.32	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 0.0134% East Asian · 6/44,884 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00242% 39/1,611,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
Admixed American	0.01%	9,987
South Asian	0.0066%	15,162
African / African-American	0.00267%	37,419
Remaining individualsnot grpmax-eligible	0.0016%	62,388
European (non-Finnish)	0.00153%	65,424

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.Ala274Thr
Coding: c.820G>A
MANE Select: NM_014889 · reported on NM_002726
Type: single nucleotide variant
Location: chr6:105352975 (GRCh38)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 274: a disulfide bond; an α-helix

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

Similar variants

PREP p.Ala274Val Uncertain significance ★ ⚠ same residue
PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Arg32Trp 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-ala274thr (accessed [today's date]).

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