Is USP2 p.Pro53Leu (c.158C>T) pathogenic?

USP2 p.Pro53Leu (c.158C>T) is classified Likely benign in USP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely benign (0.1241); Rare (popmax 0.561%, afr).

How common is USP2 p.Pro53Leu (c.158C>T) in the general population?

USP2 p.Pro53Leu (c.158C>T) is rare (popmax 0.561%, afr) (gnomAD).

What do computational predictors say about USP2 p.Pro53Leu (c.158C>T)?

AlphaMissense predicts likely benign (score 0.1241) — an in-silico prediction, not a clinical call.

USP2 p.Pro53Leu

c.158C>T · rs142496697 · VCV2642466

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1241 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.561%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1241	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -8.29	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 5.8	GERP -0.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00016 · regional, not allelic
Overall
CADD	23.4	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 0.561% African / African-American · 421/75,032 alleles

Filtering AF 0.517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.499%

Overall 0.0333% 537/1,613,370 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.561%	178
Middle Eastern	0.297%	337
Remaining individualsnot grpmax-eligible	0.088%	1,136
Admixed American	0.03%	3,334
South Asian	0.00549%	18,217
East Asian	0.00223%	44,886
European (non-Finnish)	0.00161%	62,099

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.Pro53Leu
Coding: c.158C>T
MANE Select: NM_004205
dbSNP: rs142496697
Type: single nucleotide variant
Location: chr11:119373323 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.00 · 8 PDB
Residue 53: the 'necessary for interaction with mdm4' region

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

Similar variants

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
USP2 p.Arg16Cys 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-pro53leu (accessed [today's date]).

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