On this page
RPGRIP1L
RPGRIP1 like
RPGRIP1L is located on the long (q) arm of chromosome 16, at band 16q12.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Available at Jeen Health
Clinical tests that include this
Overview
RPGRIP1L (RPGRIP1 like) is located on chromosome 16 and encodes a protein of 1,315 amino acids essential for the assembly and maintenance of primary cilia. Primary cilia are sensory organelles that detect chemical signals and mechanical cues in the cellular environment, coordinating developmental programmes across multiple organ systems. The RPGRIP1L protein localises to the transition zone, a specialised region at the ciliary base that controls which molecules enter and exit the cilium. Pathogenic variants in RPGRIP1L follow an autosomal recessive inheritance pattern, meaning two altered copies are required to cause disease. Loss of RPGRIP1L function disrupts ciliary architecture and signalling pathways critical during embryonic development, particularly affecting tissues that rely heavily on ciliary communication such as kidney tubules, retinal photoreceptors, and the developing central nervous system.
What the gene does
The RPGRIP1L protein functions as a structural scaffold within the ciliary transition zone, a gatekeeper region that maintains the distinct protein composition of the cilium compared to the rest of the cell. By organising other transition zone proteins into functional complexes, RPGRIP1L helps establish a selective barrier controlling cargo transport into the ciliary compartment. This regulatory role is essential for proper Hedgehog and Wnt signalling, two developmental pathways that depend on ciliary localisation of key receptors and signal transducers. The protein's C2 domains enable membrane association and protein-protein interactions necessary for assembling the transition zone architecture. During early development, RPGRIP1L activity coordinates left-right body patterning by facilitating ciliary flow detection in the embryonic node. In the kidney, the protein supports planar cell polarity and tubular morphogenesis by maintaining ciliary mechanosensory function. In photoreceptor cells of the retina, RPGRIP1L contributes to the connecting cilium structure that links the inner and outer segments, enabling transport of proteins required for phototransduction.
Video: Genetics 101
Chromosome location
RPGRIP1L is located on the long arm of chromosome 16 at position 16q12.2. The gene spans approximately 140 kilobases of genomic DNA and contains 27 exons. This chromosomal region has been associated with ciliopathy phenotypes through linkage studies in consanguineous families. The gene's position places it among a cluster of other genes involved in ciliary function and development.
Protein structure
The RPGRIP1L protein comprises 1,315 amino acids organised into several functional regions. Three extended coiled coil domains occupy amino acids 64-144, 197-256, and 326-555, providing structural rigidity and enabling protein-protein interactions with other transition zone components. Two C2 domains (C2 1 spanning amino acids 577-713 and C2 2 spanning amino acids 773-897) mediate calcium-dependent membrane binding and protein recognition. A disordered region between amino acids 1021 and 1083 likely confers flexibility for dynamic interactions. The coiled coil architecture allows RPGRIP1L to form elongated structures that span the transition zone, whilst the C2 domains anchor the protein to ciliary membranes and recruit binding partners essential for barrier function.
Key variants
Pathogenic variants in RPGRIP1L are predominantly loss-of-function changes including nonsense mutations, frameshift deletions or insertions, and splice-site alterations that disrupt protein production. Missense variants affecting the C2 domains or critical residues within the coiled coil regions can impair protein stability or interaction interfaces. The spectrum of pathogenic variants is distributed across the gene, with no single predominant mutation hotspot identified. Carrier frequency varies by population, with some consanguineous communities showing elevated rates due to founder effects.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in RPGRIP1L cause a spectrum of ciliopathy disorders characterised by overlapping features affecting multiple organ systems. The most severe presentations include Meckel-Gruber syndrome and Joubert syndrome, conditions with distinctive brain malformations, cystic kidney disease, retinal dystrophy, and skeletal abnormalities. COACH syndrome (cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis) represents an intermediate phenotype. Clinical severity correlates broadly with the degree of residual RPGRIP1L function, with complete loss-of-function variants typically associated with early-lethal Meckel-Gruber syndrome. Milder variants may permit survival but cause progressive kidney disease, visual impairment, and intellectual disability. The phenotypic variability reflects the pleiotropic role of primary cilia across developing and mature tissues.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic RPGRIP1L variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
RPGRIP1L holds green (high evidence) status across 13 NHS Genomic Medicine Service panels reflecting its established role in inherited disease. These include the DDG2P panel, Ductal plate malformation, Fetal anomalies (R21), Intellectual disability (R29), Neurological ciliopathies, Ocular coloboma, Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, Renal ciliopathies, Retinal disorders (R32), Skeletal dysplasia (R104), Structural eye disease (R36), and Unexplained kidney failure in young people. Green classification indicates robust evidence linking RPGRIP1L variants to these phenotypes, supporting its inclusion in diagnostic gene panel testing for patients presenting with ciliopathy features. Carrier screening for RPGRIP1L is available through accredited UK laboratories for individuals with family history or relevant ancestry.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of an RPGRIP1L variant?
Carriers have one pathogenic variant and one working copy of the gene, typically experiencing no symptoms themselves. If both biological parents are carriers, each pregnancy has a 25% chance of inheriting two altered copies and developing a ciliopathy condition.
How are RPGRIP1L-related conditions diagnosed?
Diagnosis combines clinical evaluation of characteristic features such as brain malformations visible on imaging, kidney cysts, retinal changes, and skeletal abnormalities with genetic testing confirming pathogenic variants in both RPGRIP1L copies. Prenatal diagnosis is possible when parental variants are known.
Are all RPGRIP1L variants equally severe?
No, severity depends on how much residual protein function remains. Complete loss-of-function variants typically cause severe early-onset disease, whilst hypomorphic variants allowing partial protein activity may result in milder, later-onset phenotypes with variable organ involvement.