Is USP2 p.Arg249Cys (c.745C>T) pathogenic?

USP2 p.Arg249Cys (c.745C>T) is classified Uncertain significance in USP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-19). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.0014%, nfe).

How common is USP2 p.Arg249Cys (c.745C>T) in the general population?

USP2 p.Arg249Cys (c.745C>T) is very rare (popmax 0.0014%, nfe) (gnomAD).

What do computational predictors say about USP2 p.Arg249Cys (c.745C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

USP2 p.Arg249Cys

c.745C>T · VCV3466740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0014%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -8.00	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 0.51	GERP -0.95, phastCons 0.066
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00016 · regional, not allelic
Overall
CADD	22.1	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 0.0014% European (non-Finnish) · 16/1,140,724 alleles

Filtering AF 0.00083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000672%

Overall 0.00111% 17/1,527,046 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0014%	71,295
African / African-American	0.00139%	71,922

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: USP2
Protein: p.Arg249Cys
Coding: c.745C>T
MANE Select: NM_004205
Type: single nucleotide variant
Location: chr11:119372736 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.00 · 8 PDB
Residue 249: the 'disordered' region

Full USP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP2 p.Arg249His Uncertain significance ★ ⚠ same residue
USP2 p.Glu93= Benign ★★ same type
USP2 p.Ala15Thr Uncertain significance ★ ⚠ same type
USP2 p.Ala244Thr Uncertain significance ★ ⚠ same type
USP2 p.Arg10His Uncertain significance ★ ⚠ same type
USP2 p.Arg148Trp Uncertain significance ★ ⚠ same type
USP2 p.Arg160Gln Uncertain significance ★ ⚠ same type
USP2 p.Arg168His 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/usp2-p-arg249cys (accessed [today's date]).

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