IFT74
protein-codingintraflagellar transport 74, the group of IFT-B1 complex
Gene summary
This gene encodes a core intraflagellar transport (IFT) protein which belongs to a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. This protein, together with intraflagellar transport protein 81, binds and transports tubulin within cilia and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with amyotrophic lateral sclerosis--frontotemporal dementia and Bardet-Biedl Syndrome. [provided by RefSeq, Mar 2017]
- CCDC2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~119.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014926
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0030463
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:1060191
Submitter: ClinGen
*IFT74* was first reported in relation to autosomal recessive ciliopathy-*IFT74* in 2016 (Lindstrand et al., PMID: 27486776). Variants in the *IFT74* gene have been reported in individuals with a variety of ciliopathy phenotypes including Bardet-Biedl syndrome (BBS), Joubert syndrome (JBTS), Short rib polydactyly syndrome (SRPS), Jeune asphyxiating thoracic dystrophy (ATD), and primary ciliary dysplasia (PCD) in the literature. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there were no differences in inheritance pattern, phenotypic variability, and molecular mechanism. Therefore, BBS, JBTS, SRPS, ATD, and PCD have been lumped into one disease entity. Of note, *IFT74* has also been reported in a proband with isolated spermatogenic failure 58 (PMID: 33689014). At least 11 unique variants (missense, nonsense, splicing, and deletion) that have been reported in 11 probands from 6 publications (PMIDs: 27486776, 33531668, 33748949, 34539760, 37315079, 37555648) are included in this curation. More information is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is also supported by functional studies showing ciliation defects in patient cells, and rescue in both zebrafish and mouse (PMIDs: 27486776, 33531668, 37315079). In summary, there is definitive evidence to support the relationship between *IFT74* and autosomal recessive ciliopathy-*IFT74*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders Gene Curation Expert Panel on August 27th, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0014926
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Endocrine
Rationale: Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IFT74 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025103.4. 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 | 4 | 124 | 2 | 130 | ||
| missense | 1 | 2 | 301 | 7 | 2 | 313 |
| nonsense | 15 | 12 | 1 | 28 | ||
| start loss | 1 | 1 | ||||
| frameshift | 11 | 5 | 16 | |||
| splice donor/acceptor (+/-2bp) | 1 | 16 | 8 | 25 | ||
| Total | 28 | 35 | 315 | 131 | 4 | 513 |
Highest pathogenic variant AF is 0.000176046
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079379.2 | 19 | MANE Select | |
| Ensembl | ENSP00000369402.5 | 19 | MANE Select | |
| RefSeq | NP_001092692.1 | 19 | Standard | |
| RefSeq | NP_001092693.1 | 19 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ift74 | Danio rerio | Structure: pronephric proximal convoluted tubule Quality: increased diameter abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Intraflagellar transport
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- keratinocyte development
- Notch signaling pathway
- determination of left/right symmetry
- heart development
- positive regulation of cell adhesion mediated by integrin
Molecular Function
- chromatin binding
- protein binding
- beta-tubulin binding
Cellular Component
- nucleus
- centrosome
- cilium
- intraciliary transport particle B
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000443698
- Coding exons
- 19
- Length
- 115892
- Individuals with no LoFs
- 124637
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 157
- Defined
- 124794
- p
- 0.000629
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.07 | 348 | 296 | 1.17 | 0.0000144 | 3989 |
| Missense (PolyPhen) | 67 | 59.107 | 1.1335 | 791 | ||
| Synonymous | -0.299 | 97 | 93.3 | 1.04 | 0.00000447 | 990 |
| Loss of Function | 2.17 | 26 | 41.0 | 0.634 | 0.00000212 | 507 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00047 | 0.00045 | rare |
| Latino/Admixed American | 0.00043 | 0.00041 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00023 | 0.00022 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.0011 | 0.0011 | notable |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the intraflagellar transport (IFT) complex B: together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. Binds beta-tubulin via its basic region. Required for ciliogenesis. {ECO:0000269|PubMed:23990561}.;
Recessive Scores
- pRec
- 0.0851
Intolerance Scores
- LoFtool
- 0.962
- RVIS EVS
- 1.2
- RVIS percentile EVS
- 92.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.164
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | Medium | High |