Is VPS33B p.Pro428fs (c.1283del) pathogenic?

VPS33B p.Pro428fs (c.1283del) is classified Likely pathogenic in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). Associated with cholestasis, progressive familial intrahepatic, 12.

What condition is associated with VPS33B p.Pro428fs (c.1283del)?

VPS33B p.Pro428fs (c.1283del) is associated with cholestasis, progressive familial intrahepatic, 12, arthrogryposis, renal dysfunction, and cholestasis 1, keratoderma-ichthyosis-deafness syndrome, autosomal recessive (ClinVar).

How is Progressive familial intrahepatic cholestasis inherited?

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

VPS33B p.Pro428fs

c.1283del · VCV3578185

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

cholestasis, progressive familial intrahepatic, 12

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 18 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.53	GERP -1.7

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

Variant & gene context

Gene: VPS33B
Protein: p.Pro428fs
Coding: c.1283del
MANE Select: NM_018668
Type: Deletion
Location: chr15:91002172 (GRCh38)
Gene constraint: LOEUF 0.971 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82

Full VPS33B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cholestasis, progressive familial intrahepatic, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arthrogryposis, renal dysfunction, and cholestasis 1 keratoderma-ichthyosis-deafness syndrome, autosomal recessive

For Progressive familial intrahepatic cholestasis (Orphanet):

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

Similar variants

VPS33B p.Arg542fs Pathogenic/Likely pathogenic ★★ same condition
VPS33B p.Leu81fs Pathogenic ★★ same condition
VPS33B p.Pro117fs Pathogenic ★★ same condition
VPS33B c.290-2_291del Pathogenic ★ same condition
VPS33B p.Asp450fs Pathogenic ★ same condition
VPS33B p.Lys201fs Likely pathogenic ★ same condition
VPS33B p.Lys413fs Likely pathogenic ★ same condition
VPS33B p.Leu183del 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/vps33b-p-pro428fs (accessed [today's date]).

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