Is USP53 p.Arg222Ser (c.666G>T) pathogenic?

USP53 p.Arg222Ser (c.666G>T) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9899); Absent from gnomAD v4.1.

How common is USP53 p.Arg222Ser (c.666G>T) in the general population?

USP53 p.Arg222Ser (c.666G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USP53 p.Arg222Ser (c.666G>T)?

AlphaMissense predicts likely pathogenic (score 0.9899) — an in-silico prediction, not a clinical call.

USP53 p.Arg222Ser

c.666G>T · VCV4740310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9899 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9899	likely pathogenic · top 2% in USP53
REVEL	0.3	indeterminate
SaProt	LLR -12.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.41	GERP -4.9, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USP53
Protein: p.Arg222Ser
Coding: c.666G>T
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119259916 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 222: 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-arg222ser (accessed [today's date]).

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