Is USP53 p.Arg166Cys (c.496C>T) pathogenic?

USP53 p.Arg166Cys (c.496C>T) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.1188); Ultra-rare (popmax 0.066%, mid); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Arg166Cys (c.496C>T)?

USP53 p.Arg166Cys (c.496C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Arg166Cys (c.496C>T) in the general population?

USP53 p.Arg166Cys (c.496C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about USP53 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1188) — an in-silico prediction, not a clinical call.

USP53 p.Arg166Cys

c.496C>T · VCV4197814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1188	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -9.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.31	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 0.2, phastCons 0.97
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	32.0	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 0.066% Middle Eastern · 4/6,058 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00266% 43/1,613,940 alleles · ultra-rare exomes 37/1,461,744 · genomes 6/152,196 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,514
Admixed American	0.03%	3,334
East Asian	0.00223%	44,850
European (non-Finnish)	0.00161%	62,103
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Arg166Cys
Coding: c.496C>T
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119256450 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 166: the usp domain; a UniProt-annotated variant site (in pfic7)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP53 p.Arg166His Uncertain significance ★ ⚠ same residue
USP53 p.Asn97Asp Uncertain significance ★★ ⚠ same condition
USP53 p.Asn97Ser Uncertain significance ★★ ⚠ same condition
USP53 p.Asp482His Uncertain significance ★★ ⚠ same condition
USP53 p.Ile613Thr Uncertain significance ★★ ⚠ same condition
USP53 p.Ser185Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Ser334Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Thr1046Met Uncertain significance ★★ ⚠ same condition

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-arg166cys (accessed [today's date]).

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