Is USP53 p.Arg338Ter (c.1012C>T) pathogenic?

USP53 p.Arg338Ter (c.1012C>T) is classified Pathogenic in USP53 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-02-01). Ultra-rare (popmax 0.0111%, eas); Associated with cholestasis.

What condition is associated with USP53 p.Arg338Ter (c.1012C>T)?

USP53 p.Arg338Ter (c.1012C>T) is associated with cholestasis, cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (ClinVar).

How common is USP53 p.Arg338Ter (c.1012C>T) in the general population?

USP53 p.Arg338Ter (c.1012C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

USP53 p.Arg338Ter

c.1012C>T · rs751511532 · VCV694273

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

cholestasis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 19
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,852 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000682% 11/1,613,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,970
African / African-American	0.00267%	37,432
Remaining individualsnot grpmax-eligible	0.0016%	62,476
South Asian	0.0011%	91,050
European (non-Finnish)	0.000169%	589,977

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.Arg338Ter
Coding: c.1012C>T
MANE Select: NM_001371395
dbSNP: rs751511532
Type: single nucleotide variant
Location: chr4:119267359 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 338: 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

cholestasis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

Similar variants

USP53 p.Arg111Ter Likely pathogenic ★★ same condition
USP53 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same condition
USP53 p.Arg520Ter Pathogenic ★★ same condition
USP53 p.Arg582Ter Pathogenic/Likely pathogenic ★★ same condition
USP53 p.Gly326Arg Uncertain significance ★★ ⚠ same condition
USP53 p.Thr1046Met Uncertain significance ★★ ⚠ same condition
USP53 c.237+1G>A Likely pathogenic ★ same condition
USP53 c.373-1G>A Pathogenic ★ 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-arg338ter (accessed [today's date]).

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