Is USP53 p.Phe317fs (c.951del) pathogenic?

USP53 p.Phe317fs (c.951del) is classified Pathogenic in USP53 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-22). Very rare (popmax 0.000273%, nfe); Associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss.

What condition is associated with USP53 p.Phe317fs (c.951del)?

USP53 p.Phe317fs (c.951del) is associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (ClinVar).

How common is USP53 p.Phe317fs (c.951del) in the general population?

USP53 p.Phe317fs (c.951del) is very rare (popmax 0.000273%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

USP53 p.Phe317fs

c.951del · rs2149389813 · VCV1328227

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000273%, nfe)

Conditions

cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.5	GERP -3.9

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000273% European (non-Finnish) · 3/1,099,738 alleles

Filtering AF 7.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000269% 4/1,488,500 alleles · very rare exomes 4/1,336,184 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00178%	56,096
European (non-Finnish)grpmax	0.000273%	366,580

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.Phe317fs
Coding: c.951del
MANE Select: NM_001371395
dbSNP: rs2149389813
Type: Deletion
Location: chr4:119261838 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 317: 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, progressive familial intrahepatic, 7, with or without hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive familial intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

USP53 c.145-10_168del Likely pathogenic ★★ same condition
USP53 c.822+1del Likely pathogenic ★★ same condition
USP53 p.Ser563fs Pathogenic ★★ same condition
USP53 c.372+3_372+6del Uncertain significance ★★ same condition
USP53 c.972+3_972+6del Likely pathogenic ★ same condition
USP53 p.Arg195fs Pathogenic ★ same condition
USP53 p.Gln113fs Likely pathogenic ★ same condition
USP53 p.Ser171fs 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-phe317fs (accessed [today's date]).

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