TULP1
protein-codingTUB like protein 1
Gene summary
This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]
- RP14
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010827
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010827
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013457
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010827
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013457
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018998
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013457
Submitter: ClinGen
Variants in the *TULP1* gene were first asserted in relation to autosomal recessive retinal dystrophies in 1998 (Hagstrom et al., PMID: 9462750). While the first cases were described as retinitis pigmentosa (RP 14, MIM#: 600132), subsequent publications expanded the spectrum of disease to include cases diagnosed as Leber congenital amaurosis (LCA 15, MIM#: 613843, PMID: 15024725). LCA patients present with severe visual impairment from infancy, nystagmus, and extinguished electroretinogram responses, while RP cases show later-onset night blindness and progressive peripheral vision loss. Both groups of TULP1-related retinopathies consistently show early and severe photoreceptor degeneration, consistent with a single spectrum of disease (PMID: 10440267, PMID: 17962469, PMID: 30950243). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic loss of function in the TULP1 gene product) and mode of inheritance (autosomal recessive) were also found to be consistent among the two groups of patients. Therefore, these cases have been lumped for the purposes of gene curation into a single disease entity, referred to as *TULP1*-related retinopathy. Identified disease-causing *TULP1* variants include missense, nonsense, frameshift, and splice-site variants. This curation has included genetic evidence from 4 probands and 3 families with co-segregation of the variant with affected status (PMID: 10440267, PMID: 17962469, PMID: 30950243, PMID: 38450199). The disease mechanism appears to be biallelic loss-of-function. This gene-disease relationship is also supported by experimental evidence that *TULP1* encodes TUB-Like protein 1, a member of the tubby-like protein (TULP) family that is highly specifically expressed in the retina and essential for the trafficking of rhodopsin from the inner segments through the connecting cilium to the outer segments (PMID: 17620573). TULP1 protein localizes to the periciliary region and synaptic terminals, interacting with cytoskeletal elements and vesicular transport components, such as microtubules and clathrin-associated complexes (PMID: 9462750, PMID: 36396940). Disease-causing *TULP1* variants disrupt these processes, resulting in mislocalization of phototransduction proteins and photoreceptor degeneration. *Tulp1*-knockout mice exhibit early-onset retinal degeneration with histological studies showing rapid photoreceptor loss, disrupted outer segment structure, and mislocalization of rhodopsin and cone opsins. Electroretinograms show severely diminished or absent responses (PMID: 9462750, PMID: 36396940). Zebrafish with knockout of the two orthologous genes similarly show opsin mislocalization in photoreceptor cells and severe degeneration at an early age (PMID: 36396940). In summary, *TULP1* is definitively associated with *TULP1*-related retinopathy. This association has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time wtihout the emergence of conflicting evidence. This classification was approved by the ClinGen Retinal Gene Curation Expert Panel on June 5th, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TULP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003322.6. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 202 | 1 | 213 | ||
| missense | 9 | 61 | 288 | 18 | 2 | 378 |
| nonsense | 22 | 10 | 1 | 33 | ||
| start loss | 1 | 1 | ||||
| frameshift | 35 | 22 | 2 | 59 | ||
| splice donor/acceptor (+/-2bp) | 5 | 20 | 1 | 26 | ||
| Total | 71 | 114 | 302 | 220 | 3 | 710 |
Highest pathogenic variant AF is 0.00015927278
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003313.3 | 15 | MANE Select | |
| Ensembl | ENSP00000229771.6 | 15 | MANE Select | |
| RefSeq | NP_001276324.1 | 14 | Standard | |
| Ensembl | ENSP00000319414.4 | 14 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- retina homeostasis
- phagocytosis, recognition
- visual perception
- dendrite development
- eye photoreceptor cell development
Molecular Function
- protein binding
- phosphatidylinositol-4,5-bisphosphate binding
- phosphatidylinositol binding
- actin filament binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- extracellular region
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000229771
- Coding exons
- 15
- Length
- 15065
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 31
- Defined
- 125748
- p
- 0.000123
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.647 | 295 | 328 | 0.899 | 0.0000214 | 3469 |
| Missense (PolyPhen) | 105 | 129.61 | 0.81011 | 1342 | ||
| Synonymous | 0.859 | 125 | 138 | 0.907 | 0.00000931 | 1079 |
| Loss of Function | 3.22 | 11 | 30.1 | 0.366 | 0.00000180 | 338 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00018 | rare |
| Latino/Admixed American | 0.00018 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00011 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for normal development of photoreceptor synapses. Required for normal photoreceptor function and for long- term survival of photoreceptor cells. Interacts with cytoskeleton proteins and may play a role in protein transport in photoreceptor cells (By similarity). Binds lipids, especially phosphatidylinositol 3-phosphate, phosphatidylinositol 4- phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-bisphosphate, phosphatidylserine and phosphatidic acid (in vitro). Contribute to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages. {ECO:0000250, ECO:0000269|PubMed:16303976, ECO:0000269|PubMed:19837063}.;
- Disease
- DISEASE: Leber congenital amaurosis 15 (LCA15) [MIM:613843]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:15024725, ECO:0000269|PubMed:17962469}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.152
Intolerance Scores
- LoFtool
- 0.104
- RVIS EVS
- -0.04
- RVIS percentile EVS
- 50.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.614
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |