Is USP2 p.Pro522Ser (c.1564C>T) pathogenic?

USP2 p.Pro522Ser (c.1564C>T) is classified Uncertain significance in USP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: ambiguous (0.559); Very rare (popmax 0.000678%, nfe).

How common is USP2 p.Pro522Ser (c.1564C>T) in the general population?

USP2 p.Pro522Ser (c.1564C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about USP2 p.Pro522Ser (c.1564C>T)?

AlphaMissense predicts ambiguous (score 0.559) — an in-silico prediction, not a clinical call.

USP2 p.Pro522Ser

c.1564C>T · VCV3814089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
AlphaMissense	0.559	ambiguous
REVEL	0.592	indeterminate
SaProt	LLR -11.83	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00016 · regional, not allelic
Overall
CADD	28.4	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 0.000678% European (non-Finnish) · 8/1,180,034 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,040 alleles · very rare exomes 8/1,461,866 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)grpmax	0.000678%	147,504

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_004205
Type: single nucleotide variant
Location: chr11:119357528 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.00 · 8 PDB
Residue 522: the usp domain

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-pro522ser (accessed [today's date]).

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