Is PREP p.His333Arg (c.998A>G) pathogenic?

PREP p.His333Arg (c.998A>G) is classified Uncertain significance in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). AlphaMissense: likely benign (0.29); Very rare (popmax 0.00153%, nfe).

How common is PREP p.His333Arg (c.998A>G) in the general population?

PREP p.His333Arg (c.998A>G) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about PREP p.His333Arg (c.998A>G)?

AlphaMissense predicts likely benign (score 0.29) — an in-silico prediction, not a clinical call.

PREP p.His333Arg

c.998A>G · rs1230264646 · VCV2238425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.29 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.29	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -8.57	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 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 117 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	24.0	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 0.00153% European (non-Finnish) · 18/1,179,914 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,968 alleles · very rare exomes 15/1,461,732 · genomes 3/152,236 · joint denominator

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.His333Arg
Coding: c.998A>G
MANE Select: NM_002726
dbSNP: rs1230264646
Type: single nucleotide variant
Location: chr6:105333331 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 17 PDB
Residue 333: an α-helix

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-his333arg (accessed [today's date]).

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