TJP2

Chr 9AR

tight junction protein 2

Also known as: C9DUPq21.11, DFNA51, DUP9q21.11, FHCA1, PFIC4, X104, ZO2

NCBI Gene: 9414ENSG00000119139UniProt: Q9UDY2

This gene encodes a zonula occluden that is a member of the membrane-associated guanylate kinase homolog family. The encoded protein functions as a component of the tight junction barrier in epithelial and endothelial cells and is necessary for proper assembly of tight junctions. Mutations in this gene have been identified in patients with hypercholanemia, and genomic duplication of a 270 kb region including this gene causes autosomal dominant deafness-51. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Primary Disease Associations & Inheritance

Cholestasis, progressive familial intrahepatic 4MIM #615878
AR
Hypercholanemia, familial 1MIM #607748
AR
975
ClinVar variants
44
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— TJP2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
44 Pathogenic / Likely Pathogenic· 296 VUS of 975 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.64LOEUF
pLI 0.000
Z-score 3.87
OE 0.46 (0.34–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.57Z-score
OE missense 0.94 (0.88–1.00)
700 obs / 743.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.46 (0.34–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.88–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 28 / 60.4Missense obs/exp: 700 / 743.5Syn Z: 0.76

ClinVar Variant Classifications

975 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic21
VUS296
Likely Benign124
Benign4
Conflicting6
23
Pathogenic
21
Likely Pathogenic
296
VUS
124
Likely Benign
4
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
1
14
0
23
Likely Pathogenic
12
4
4
1
21
VUS
1
274
20
1
296
Likely Benign
0
0
56
68
124
Benign
0
1
3
0
4
Conflicting
—6
Total212809770474

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TJP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cholestasis, progressive familial intrahepatic 4

MIM #615878

Molecular basis of disorder known

Autosomal recessive

Hypercholanemia, familial 1

MIM #607748

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Overview of Progressive Familial Intrahepatic Cholestasis.
Hassan S et al.·Clin Liver Dis
2022Review
Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases.
Chen HL et al.·J Biomed Sci
2018Review
Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.
Lal BB et al.·Hepatology
2024
TJP2 hepatobiliary disorders: Novel variants and clinical diversity.
Zhang J et al.·Hum Mutat
2020
ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation.
Yang W et al.·Cell Death Dis
2023
Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing.
Vitale G et al.·J Gastroenterol
2018
Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct.
Bernardinelli E et al.·Mol Med
2025Cohort
Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level.
Khabou B et al.·J Hum Genet
2025Case report
Clinical and Genetic Spectra of Progressive Familial Intrahepatic Cholestasis With Normal GGT: 31 Pediatric Patients and 16 Novel Variants.
Elkoofy NM et al.·Clin Genet
2026Cohort
The Mutational Landscape Of Genetic Cholestatic Diseases In Pakistani Children.
Cheema HA et al.·J Pak Med Assoc
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
PFIC - Progressive Familial Intrahepatic CholestasisAlagille Syndrome (ALGS)Cholestasis, Intrahepatic

Pediatric Evaluation and Registry for Liver Cholestasis in Canada

NOT YET RECRUITING
NCT07411716Children's Hospital of Eastern OntarioStarted 2026-03

External Resources

Links to major genomics databases and tools