Is USP53 p.Pro225= (c.675T>C) pathogenic?

USP53 p.Pro225= (c.675T>C) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-13). Ultra-rare (popmax 0.0147%, afr).

How common is USP53 p.Pro225= (c.675T>C) in the general population?

USP53 p.Pro225= (c.675T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

USP53 p.Pro225=

c.675T>C · VCV3627556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -5.2
Overall
CADD	10.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,664 alleles

Filtering AF 0.00818% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.00144% 23/1,601,880 alleles · ultra-rare exomes 18/1,449,516 · genomes 5/152,364 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0194%	5,158
African / African-Americangrpmax	0.0147%	6,788

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: USP53
Protein: p.Pro225=
Coding: c.675T>C
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119259925 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 225: the usp domain; a UniProt-annotated variant site (in pfic7)

Full USP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP53 p.Arg111Ter Likely pathogenic ★★ same type
USP53 p.Arg338Ter Pathogenic ★★ same type
USP53 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same type
USP53 p.Arg520Ter Pathogenic ★★ same type
USP53 p.Arg582Ter Pathogenic/Likely pathogenic ★★ same type
USP53 p.Arg58Gln Uncertain significance ★★ ⚠ same type
USP53 p.Asn97Asp Uncertain significance ★★ ⚠ same type
USP53 p.Asn97Ser 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/usp53-p-pro225 (accessed [today's date]).

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