Is TJP2 p.Ser415fs (c.1243del) pathogenic?

TJP2 p.Ser415fs (c.1243del) is classified Pathogenic in TJP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-07-01). Very rare (popmax 8.48e-05%, nfe); Associated with cholestasis, progressive familial intrahepatic, 4.

What condition is associated with TJP2 p.Ser415fs (c.1243del)?

TJP2 p.Ser415fs (c.1243del) is associated with cholestasis, progressive familial intrahepatic, 4 (ClinVar).

How common is TJP2 p.Ser415fs (c.1243del) in the general population?

TJP2 p.Ser415fs (c.1243del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

TJP2 p.Ser415fs

c.1243del · rs1057518679 · VCV374295

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

cholestasis, progressive familial intrahepatic, 4

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 8 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.7	GERP -4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,100 alleles

Overall 6.2e-05% 1/1,612,884 alleles · very rare exomes 1/1,460,712 · genomes 0/152,172 · 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: TJP2
Protein: p.Ser415fs
Coding: c.1243del
MANE Select: NM_004817
dbSNP: rs1057518679
Type: Deletion
Location: chr9:69227794 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.92 · 2 PDB
Residue 415: a modified residue (phosphoserine); the 'disordered' region

Full TJP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cholestasis, progressive familial intrahepatic, 4 — 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

TJP2 p.Arg775_Leu776insTer Pathogenic/Likely pathogenic ★★ same condition
TJP2 p.Tyr261fs Pathogenic ★★ same condition
TJP2 p.Arg197_Ser200del Uncertain significance ★★ same condition
TJP2 c.1672-27del Benign ★★ same condition
TJP2 c.1517_1520+8del Likely pathogenic ★ same condition
TJP2 p.Ala273fs Pathogenic ★ same condition
TJP2 p.Ala454fs Pathogenic ★ same condition
TJP2 p.Arg42fs 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/tjp2-p-ser415fs (accessed [today's date]).

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