GeneBe

TULP3

protein-coding

TUB like protein 3

Gene summary

This gene encodes a member of the tubby gene family of bipartite transcription factors. Members of this family have been identified in plants, vertebrates, and invertebrates, and they share a conserved N-terminal transcription activation region and a conserved C-terminal DNA and phosphatidylinositol-phosphate binding region. The encoded protein binds to phosphoinositides in the plasma membrane via its C-terminal region and probably functions as a membrane-bound transcription regulator that translocates to the nucleus in response to phosphoinositide hydrolysis, for instance, induced by G-protein-coupled-receptor signaling. It plays an important role in neuronal development and function. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2009]

MANE transcript

NM_003324.5

Inheritance

AR

ClinVar variants

P:12U:75B:20

Top phenotype

Hepatorenocardiac degenerative fibrosis

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr12:2,877,223-2,941,138

External References & Databases

Ensembl (ENSG00000078246)NCBI Gene (7289)OMIM (604730)HGNC:12425GenCCUniProt (O75386)AlphaFoldClinVar (TULP3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~63.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hepatorenocardiac degenerative fibrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859254

Submitter: Labcorp Genetics (formerly Invitae)

hepatorenocardiac degenerative fibrosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859254

Submitter: Ambry Genetics

hepatorenocardiac degenerative fibrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859254

Submitter: PanelApp Australia

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*TULP3* was first reported in relation to an autosomal recessive ciliopathy in 2022 (Devane et al., PMID: 35397207) now commonly referred to as hepatorenocardiac degenerative fibrosis. This condition was characterized by progressive degenerative liver fibrosis and fibrocystic kidney disease. Some reported probands also have hypertrophic cardiomyopathy, but a specific association with this phenotype remains to be confirmed on a larger scale. Additional features included portal hypertension, hepatosplenomegaly, elevated liver enzymes, esophageal varices, abnormal blood counts, and cholestasis. Eight variants (missense, nonsense, frameshift, intragenic deletion, splice site) reported in eight probands and additional family members in a publication (PMID: 35397207) were scored in this curation. Variants in this gene segregated with disease in at least three additional family members. Since the inaugural cohort, there have been new reports of patients with *TULP3* variants and the reported phenotype (PMID: 40066670, PMID: 39183737). Additionally, there have been recent reports of *TULP3* patients with overlapping phenotypes and new features such as chronic tubulointerstitial nephropathy, and neurologic manifestations (PMID: 36460032, PMID: 40579123), suggesting a wider phenotype variability that may also include isolated renal and hepatic features. Age of onset is reported as early as 10 days after birth to late adulthood, with liver disease tending to develop earlier and cardiac disease develop later. This gene-disease association has been supported by experimental evidence showing that the mechanism of pathogenicity appears to be loss of function (LOF). Animal models, with data from mice (Legue et al., 2019; PMID: 30799240 and Hwang et al., 2019; PMID: 30799239) and zebrafish models (Devane et al., 2022; PMID: 35397207); as well as expression studies also support this gene-disease relationship (PMIDs: 35397207, 30799240, 30799239, 9828123). In summary, *TULP3* is Definitively associated with autosomal recessive ciliopathy-*TULP3*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 06/24/2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Hepatorenocardiac degenerative fibrosisAR

Manifestation: Cardiovascular; Gastrointestinal; Renal

Intervention: Cardiovascular; Gastrointestinal; Renal

Rationale: The condition can involve fibrosis affecting multiple organ systems, and medical care (eg, related to cardiac fibrosis) may be beneficial; Liver and renal transplant have been described

Refs: 35397207Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TULP3 variants in ClinVar

5 Conditions Cataloged
Inborn genetic diseasesTotal: 69
TULP3-related conditionTotal: 15
Hepatorenocardiac degenerative fibrosisTotal: 12
not providedTotal: 11
not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003324.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
7
clinvar
 8
missense
2
clinvar
1
clinvar
71
clinvar
11
clinvar
2
clinvar
 87
nonsense
1
clinvar
1
clinvar
 2
start loss
0
frameshift
1
clinvar
2
clinvar
 3
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
3
clinvar
 7
Total6675182107

Highest pathogenic variant AF is 0.00016590534

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003324.5RefSeqNP_003315.211MANE Select
ENST00000448120.7EnsemblENSP00000410051.211MANE Select
NM_001160408.2RefSeqNP_001153880.112Standard
ENST00000397132.6EnsemblENSP00000380321.212Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • H19 action Rb-E2F1 signaling and CDK-β-catenin activity
  • Signal Transduction
  • Hedgehog ,off, state
  • Signaling by Hedgehog

Biological Process

  • neural tube closure
  • regulation of transcription, DNA-templated
  • G protein-coupled receptor signaling pathway
  • brain development
  • regulation of G protein-coupled receptor signaling pathway

Molecular Function

  • protein binding
  • phosphatidylinositol-4,5-bisphosphate binding
  • enzyme binding
  • phosphatidylinositol binding
  • protein-containing complex binding

Cellular Component

  • extracellular region
  • nucleus
  • nucleolus
  • plasma membrane
  • cilium

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000397132
Coding exons
12
Length
63918
Individuals with no LoFs
125614
Homozygous LoFs
0
Heterozygous LoFs
133
Defined
125747
p
0.000529
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2572832950.9580.00001713289
Missense (PolyPhen)7981.6090.96803904
Synonymous-0.4781091031.060.00000571973
Loss of Function2.011323.50.5530.00000136271

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000200.00018rare
Latino/Admixed American0.000650.00061rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000710.00069rare
South Asian0.000780.00075rare
Other0.000810.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein- coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh signaling. Binds to phosphorylated inositide (phosphoinositide) lipids. Both IFT- A- and phosphoinositide-binding properties are required to regulate ciliary G protein-coupled receptor trafficking. Not involved in ciliogenesis. {ECO:0000269|PubMed:11375483, ECO:0000269|PubMed:20889716}.;

Recessive Scores

pRec
0.107

Intolerance Scores

LoFtool
0.0909
RVIS EVS
0.24
RVIS percentile EVS
69.51

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.725

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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