Is VPS33B p.Pro412fs (c.1235_1236delinsG) pathogenic?

VPS33B p.Pro412fs (c.12351236delinsG) is classified Pathogenic in VPS33B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). Associated with cholestasis, progressive familial intrahepatic, 12.

What condition is associated with VPS33B p.Pro412fs (c.1235_1236delinsG)?

VPS33B p.Pro412fs (c.1235_1236delinsG) 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.Pro412fs

c.1235_1236delinsG · VCV3578187

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

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 17 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP -0.16, phastCons 1

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

Variant & gene context

Gene: VPS33B
Protein: p.Pro412fs
Coding: c.1235_1236delinsG
MANE Select: NM_018668
Type: Indel
Location: chr15:91003121 (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.Glu614Leu Uncertain significance ★★ same condition
VPS33B p.Leu45_Met46delinsIleLeu Uncertain significance ★★ same condition
VPS33B c.1106-35_1106-7delinsGGT Pathogenic ★ same condition
VPS33B p.Arg585fs Likely pathogenic ★ same condition
VPS33B p.Gly131Glu Likely pathogenic ★ same condition
VPS33B c.1030+1G>A Likely pathogenic ★★ same condition
VPS33B c.1225+5G>C Pathogenic/Likely pathogenic ★★ same condition
VPS33B c.239+5G>A Pathogenic/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/vps33b-p-pro412fs (accessed [today's date]).

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