TJP1

Chr 15

tight junction protein 1

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

TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton (PubMed:7798316, PubMed:9792688). Forms a multistranded TJP1/ZO1 condensate which elongates to form a tight junction belt, the belt is anchored at the apical cell membrane via interaction with PATJ (By similarity). The tight junction acts to limit movement of substances through the paracellular space and as a boundary between the compositionally distinct apical and basolateral plasma membrane domains of epithelial and endothelial cells. Necessary for lumenogenesis, and particularly efficient epithelial polarization and barrier formation (By similarity). Plays a role in the regulation of cell migration by targeting CDC42BPB to the leading edge of migrating cells (PubMed:21240187). Plays an important role in podosome formation and associated function, thus regulating cell adhesion and matrix remodeling (PubMed:20930113). With TJP2 and TJP3, participates in the junctional retention and stability of the transcription factor DBPA, but is not involved in its shuttling to the nucleus (By similarity). May play a role in mediating cell morphology changes during ameloblast differentiation via its role in tight junctions (By similarity)

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Limited · arrhythmogenic right ventricular cardiomyopathy · AD · ClinGen 2019

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

144

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.07

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

Background carrier burden — how many people carry a rare variant somewhere in TJP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

2,320 rare PASS variants

Rare truncating (LoF)

1 in 1,500

142 rare PASS variants

Rare synonymous (reference)

1 in 58

932 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TJP1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 41	1 in 1,600
South Asian	~43k	1 in 27	1 in 1,900
Remaining (unassigned)	~30k	1 in 22	1 in 300
European (Finnish)	~27k	1 in 77	1 in 1,500
Admixed American	~22k	1 in 26	1 in 430
African / African American	~21k	1 in 26	1 in 610
East Asian	~20k	1 in 28	1 in 2,400
Ashkenazi Jewish	~13k	1 in 140	1 in 1,400
Middle Eastern	~2,884	1 in 25	≈ 1 in 1,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 26 of 28 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: 27 of 28 (exon 22 below).? see exons ↓