TJP1

Chr 15

tight junction protein 1

Also known as: ZO-1

NCBI Gene: 7082 ENSG00000104067 UniProt: Q07157 OMIM: 601009

TJP1 encodes a tight junction scaffolding protein that links transmembrane proteins to the actin cytoskeleton, regulating the movement of substances between epithelial and endothelial cells and maintaining cell polarity. Mutations cause autosomal dominant progressive familial intrahepatic cholestasis type 4, which presents in infancy with cholestasis, pruritus, and progressive liver disease. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.071), indicating that haploinsufficiency is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, and acts as a tight junction adaptor protein that also regulates adherens junctions. Tight junctions regulate the movement of ions and macromolecules between endothelial and epithelial cells. The multidomain structure of this scaffold protein, including a postsynaptic density 95/disc-large/zona occludens (PDZ) domain, a Src homology (SH3) domain, a guanylate kinase (GuK) domain and unique (U) motifs all help to co-ordinate binding of transmembrane proteins, cytosolic proteins, and F-actin, which are required for tight junction function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.07

Clinical Summary— TJP1

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

257 VUS of 323 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 8.52

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.54Z-score

OE missense 0.86 (0.81–0.91)

829 obs / 963.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.07)

0≤0.351.4

Missense OE?0.86 (0.81–0.91)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 88.4Missense obs/exp: 829 / 963.7Syn Z: -0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedTJP1-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

This gene — mechanism propensity

0.3495th %ile

GOF

0.4382th %ile

LOF

0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.07

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

323 submitted variants in ClinVar

ClinVar

Classification Summary

VUS257

Likely Benign24

Benign15

Conflicting2

257

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	257	0	0	257
Likely Benign	0	7	3	14	24
Benign	0	4	3	8	15
Conflicting	—				2
Total	0	268	6	22	298

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 148) ClinVar copy-number / structural variants overlap TJP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →