Is USP53 p.Val49Asp (c.146T>A) pathogenic?

USP53 p.Val49Asp (c.146T>A) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9833); Absent from gnomAD v4.1; Associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss.

What condition is associated with USP53 p.Val49Asp (c.146T>A)?

USP53 p.Val49Asp (c.146T>A) is associated with cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (ClinVar).

How common is USP53 p.Val49Asp (c.146T>A) in the general population?

USP53 p.Val49Asp (c.146T>A) is absent from gnomAD v4.1 (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.Val49Asp (c.146T>A)?

AlphaMissense predicts likely pathogenic (score 0.9833) — an in-silico prediction, not a clinical call.

USP53 p.Val49Asp

c.146T>A · rs2530265240 · VCV3065121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9833 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9833	likely pathogenic · top 3% in USP53
REVEL	0.765	pathogenic-leaning
SaProt	LLR -16.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	29.8	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.Val49Asp
Coding: c.146T>A
MANE Select: NM_001371395
dbSNP: rs2530265240
Type: single nucleotide variant
Location: chr4:119245338 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 49: the usp domain; a UniProt-annotated variant site (in pfic7; uncertain significance)

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-val49asp (accessed [today's date]).

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