Is USP53 p.Ser654Arg (c.1962T>A) pathogenic?

USP53 p.Ser654Arg (c.1962T>A) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.6056); Very rare (popmax 0.0011%, sas); Associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss.

What condition is associated with USP53 p.Ser654Arg (c.1962T>A)?

USP53 p.Ser654Arg (c.1962T>A) is associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (ClinVar).

How common is USP53 p.Ser654Arg (c.1962T>A) in the general population?

USP53 p.Ser654Arg (c.1962T>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

What do computational predictors say about USP53 p.Ser654Arg (c.1962T>A)?

AlphaMissense predicts likely pathogenic (score 0.6056) — an in-silico prediction, not a clinical call.

USP53 p.Ser654Arg

c.1962T>A · VCV3367150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6056	likely pathogenic
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.034	GERP -2.1, phastCons 0.96
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,710 alleles

Overall 6.2e-05% 1/1,612,626 alleles · very rare exomes 1/1,460,434 · genomes 0/152,192 · joint denominator

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.Ser654Arg
Coding: c.1962T>A
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119271822 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 654: 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 p.Arg111Ter Likely pathogenic ★★ same condition
USP53 p.Arg338Ter 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

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-ser654arg (accessed [today's date]).

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