IFT74

Summary

IFT74 (intraflagellar transport 74, HGNC:21424) is a protein-coding gene on chromosome 9p21.2, encoding Intraflagellar transport protein 74 homolog (Q96LB3). 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.

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.

Source: NCBI Gene 80173 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy-IFT74 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 742 total — 41 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 147
• MANE Select transcript: NM_025103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21424
Approved symbol	IFT74
Name	intraflagellar transport 74
Location	9p21.2
Locus type	gene with protein product
Status	Approved
Aliases	CMG1, CMG-1, FLJ22621
Ensembl gene	ENSG00000096872
Ensembl biotype	protein_coding
OMIM	608040
Entrez	80173

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000380062, ENST00000429045, ENST00000433700, ENST00000443698, ENST00000482986, ENST00000494236, ENST00000517444, ENST00000517866, ENST00000518614, ENST00000519968, ENST00000648373, ENST00000903173

RefSeq mRNA: 5 — MANE Select: NM_025103 NM_001099222, NM_001099223, NM_001099224, NM_001349928, NM_025103

CCDS: CCDS43793, CCDS47955

Canonical transcript exons

ENST00000380062 — 20 exons

Exon	Start	End
ENSE00000620910	27056334	27056459
ENSE00000694318	27048148	27048274
ENSE00000694379	27055609	27055772
ENSE00001169707	27060591	27060651
ENSE00001291483	27029025	27029104
ENSE00001294377	27016907	27017050
ENSE00001316343	27011906	27011968
ENSE00001316870	27018647	27018687
ENSE00001319820	26990134	26990195
ENSE00001321793	27009020	27009158
ENSE00001377631	26978128	26978263
ENSE00001385197	26984257	26984355
ENSE00001390886	26980571	26980619
ENSE00001483658	26961949	26962087
ENSE00001822336	26956412	26956516
ENSE00001867256	27062618	27066134
ENSE00003498317	27047274	27047371
ENSE00003575127	27044742	27044795
ENSE00003657816	26984499	26984559
ENSE00003789670	26988669	26988728

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 93.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5803 / max 401.9012, expressed in 1763 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96353	12.2933	1728
96351	0.9707	569
205449	0.2550	99
96354	0.0613	13

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	93.38	gold quality
caput epididymis	UBERON:0004358	92.38	gold quality
right uterine tube	UBERON:0001302	92.15	gold quality
calcaneal tendon	UBERON:0003701	92.14	gold quality
epithelium of bronchus	UBERON:0002031	91.05	gold quality
corpus epididymis	UBERON:0004359	90.68	gold quality
left testis	UBERON:0004533	90.55	gold quality
bronchus	UBERON:0002185	90.27	gold quality
right testis	UBERON:0004534	90.10	gold quality
testis	UBERON:0000473	89.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.96	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.84	gold quality
ventricular zone	UBERON:0003053	88.51	gold quality
adrenal tissue	UBERON:0018303	88.16	gold quality
sperm	CL:0000019	87.90	gold quality
metanephros cortex	UBERON:0010533	86.82	gold quality
rectum	UBERON:0001052	86.08	gold quality
tendon	UBERON:0000043	85.99	gold quality
cauda epididymis	UBERON:0004360	85.76	gold quality
right adrenal gland cortex	UBERON:0035827	85.75	gold quality
right adrenal gland	UBERON:0001233	85.67	gold quality
left lobe of thyroid gland	UBERON:0001120	85.30	gold quality
male germ cell	CL:0000015	85.23	gold quality
colonic epithelium	UBERON:0000397	85.21	gold quality
adenohypophysis	UBERON:0002196	85.16	gold quality
left adrenal gland	UBERON:0001234	85.05	gold quality
islet of Langerhans	UBERON:0000006	84.99	gold quality
thyroid gland	UBERON:0002046	84.99	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.00
E-GEOD-100618	no	548.80
E-GEOD-75367	no	123.08
E-CURD-112	no	2.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting IFT74, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-7158-3P	98.46	66.45	728
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-6509-5P	97.39	68.27	969

Literature-anchored findings (GeneRIF, showing 8)

• The results revealed that the common variations in IFT74 and GRN neither constitute strong ALS risk factors nor modify the age-at-onset. (PMID:17383054)
• this study found that the two core intraflagellar transport proteins IFT74 and IFT81 form a tubulin-binding module and mapped the interaction to a calponin homology domain of IFT81 and a highly basic domain in IFT74. (PMID:23990561)
• Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome. (PMID:33531668)
• A missense mutation in IFT74, encoding for an essential component for intraflagellar transport of Tubulin, causes asthenozoospermia and male infertility without clinical signs of Bardet-Biedl syndrome. (PMID:33689014)
• Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74. (PMID:33748949)
• Impaired cooperation between IFT74/BBS22-IFT81 and IFT25-IFT27/BBS19 causes Bardet-Biedl syndrome. (PMID:34888642)
• IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans. (PMID:37315079)
• Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations. (PMID:37555648)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ift74	ENSDARG00000023495
mus_musculus	Ift74	ENSMUSG00000028576
rattus_norvegicus	Ift74	ENSRNOG00000008075
caenorhabditis_elegans		WBGENE00016005

Protein

Protein identifiers

Intraflagellar transport protein 74 homolog — Q96LB3 (reviewed: Q96LB3)

Alternative names: Capillary morphogenesis gene 1 protein, Coiled-coil domain-containing protein 2

All UniProt accessions (6): A0A3B3IT46, E5RGX6, E5RH29, E5RIF0, E5RJK3, Q96LB3

UniProt curated annotations — full annotation on UniProt →

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. Essential for flagellogenesis during spermatogenesis.

Subunit / interactions. Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88. Interacts with IFT81; the interaction is direct. Within the IFT complex B, IFT74 and IFT81 mediate the transport of tubulin within the cilium. Interacts (via basic region) with beta-tubulin (via acidic region); interaction is direct. Interacts with ARL13B and IFT88. Interacts (via the IFT74/IFT81 heterodimer) with RABL2B. Interacts with IFT57 and IFT70B.

Subcellular location. Cell projection. Cilium. Cytoplasmic vesicle. Flagellum. Secretory vesicle. Acrosome.

Tissue specificity. Highly expressed in adult and fetal kidney and expressed at lower level in adult heart, placenta, lung, liver and pancreas, and in fetal heart, lung and liver. Little to no expression was detected in adult brain and skeletal muscle or in fetal brain, thymus and spleen. Detected in sperm (at protein level).

Disease relevance. Bardet-Biedl syndrome 22 (BBS22) [MIM:617119] A form of Bardet-Biedl syndrome, a syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry. Joubert syndrome 40 (JBTS40) [MIM:619582] A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS40 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Spermatogenic failure 58 (SPGF58) [MIM:619585] An autosomal recessive male infertility disorder characterized by absent or severely reduced sperm motility, due to multiple morphological abnormalities of the sperm flagellum. The disease is caused by variants affecting the gene represented in this entry. A homozygous variant at codon 86 has been identified in 2 unrelated affected individuals. In addition to encoding a missense, this variant also affects splicing, predominantly through the induction of an in-frame deletion of 10 amino acids within exon 3. Other minor transcripts can be detected in patient’s sperm that use cryptic donor sites present in intron 3, leading either to the retention of 18 bp of intron 3 and an in-frame insertion of 6 amino acids, or to the retention of 108 bp of intron 3, which induces a frameshift and a truncated protein.

Similarity. Belongs to the IFT74 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96LB3-1	1	yes
Q96LB3-2	2

RefSeq proteins (5): NP_001092692, NP_001092693, NP_001092694, NP_001336857, NP_079379* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029602	IFT74	Family

UniProt features (20 total): sequence variant 11, region of interest 3, modified residue 2, chain 1, sequence conflict 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LB3-F1	81.21	0.48

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 51, 73

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5620924	Intraflagellar transport

MSigDB gene sets: 479 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOCC_SECRETORY_GRANULE, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CILIUM_ORGANIZATION, GOBP_REGULATION_OF_CELL_ADHESION_MEDIATED_BY_INTEGRIN, GOCC_CENTROSOME

GO Biological Process (16): keratinocyte development (GO:0003334), Notch signaling pathway (GO:0007219), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), negative regulation of keratinocyte proliferation (GO:0010839), positive regulation of cell adhesion mediated by integrin (GO:0033630), intraciliary anterograde transport (GO:0035720), intraciliary transport involved in cilium assembly (GO:0035735), keratinocyte proliferation (GO:0043616), positive regulation of transcription by RNA polymerase II (GO:0045944), cilium assembly (GO:0060271), non-motile cilium assembly (GO:1905515), epidermis development (GO:0008544), cell projection organization (GO:0030030), intraciliary transport (GO:0042073), negative regulation of epithelial cell proliferation (GO:0050680)

GO Molecular Function (3): chromatin binding (GO:0003682), beta-tubulin binding (GO:0048487), protein binding (GO:0005515)

GO Cellular Component (10): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), centrosome (GO:0005813), cilium (GO:0005929), intraciliary transport particle A (GO:0030991), intraciliary transport particle B (GO:0030992), motile cilium (GO:0031514), ciliary tip (GO:0097542), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cilium	3
intraciliary transport particle	3
intraciliary transport	2
cilium assembly	2
epithelial cell proliferation	2
cilium organization	2
binding	2
protein-containing complex	2
cellular anatomical structure	2
epithelial cell development	1
keratinocyte differentiation	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
animal organ development	1
circulatory system development	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
positive regulation of cell adhesion	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
tissue development	1
cellular component organization	1
transport along microtubule	1
negative regulation of cell population proliferation	1
regulation of epithelial cell proliferation	1
tubulin binding	1
secretory granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1613 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFT74	IFT81	Q8WYA0	998
IFT74	IFT46	Q9NQC8	996
IFT74	IFT27	Q9BW83	996
IFT74	IFT52	Q9Y366	995
IFT74	IFT22	Q9H7X7	994
IFT74	IFT88	Q13099	992
IFT74	IFT70B	Q8N4P2	990
IFT74	IFT25	Q9Y547	986
IFT74	IFT54	Q8TDR0	973
IFT74	IFT57	Q9NWB7	972
IFT74	IFT80	Q9P2H3	964
IFT74	IFT172	Q9UG01	940
IFT74	IFT20	Q8IY31	939
IFT74	IFT56	A0AVF1	859
IFT74	TTC21B	Q7Z4L5	858

IntAct

139 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
DTNB	DMD	psi-mi:“MI:0914”(association)	0.890
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
IFT56	IFT70A	psi-mi:“MI:0914”(association)	0.790
IFT70A	IFT56	psi-mi:“MI:0914”(association)	0.790
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
IFT25	IFT56	psi-mi:“MI:0914”(association)	0.690
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
IFT22	IFT56	psi-mi:“MI:0914”(association)	0.640
IFT46	IFT56	psi-mi:“MI:0914”(association)	0.640
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640

BioGRID (185): IFT74 (Affinity Capture-MS), IFT74 (Affinity Capture-MS), IFT74 (Affinity Capture-MS), IFT74 (Affinity Capture-MS), IFT74 (Affinity Capture-MS), IFT74 (Affinity Capture-MS), IFT74 (Proximity Label-MS), IFT74 (Affinity Capture-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS), IFT74 (Proximity Label-MS)

ESM2 similar proteins: A1A5Q4, A4IH82, A6H782, A7S8T5, F7F3Q2, G5E8A8, O35594, O46469, Q0E908, Q149S1, Q26648, Q29RL1, Q2T9Q6, Q2TA16, Q2TA38, Q2YDI7, Q32KZ9, Q3SYS9, Q4R353, Q4R5V1, Q4R7G7, Q4V8G8, Q5PPV2, Q5RHQ8, Q5U584, Q5XIJ8, Q6AXV2, Q6AYM2, Q6DFJ6, Q6DGZ3, Q6PE87, Q6X6Z7, Q8CI04, Q8IXS2, Q8IYR0, Q8VHI7, Q8WW24, Q8WYA0, Q922G7, Q95JU3

Diamond homologs: Q8BKE9, Q96LB3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intraflagellar transport	14	40.6×	6e-17
Loss of Nlp from mitotic centrosomes	8	18.4×	1e-06
Loss of proteins required for interphase microtubule organization from the centrosome	8	18.4×	1e-06
Hedgehog ‘off’ state	7	18.1×	6e-06
Anchoring of the basal body to the plasma membrane	11	18.0×	4e-09
AURKA Activation by TPX2	8	17.6×	1e-06
Regulation of PLK1 Activity at G2/M Transition	9	16.6×	5e-07
Recruitment of mitotic centrosome proteins and complexes	8	15.8×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
intraciliary anterograde transport	13	121.4×	5e-23
intraciliary transport	12	71.0×	9e-18
non-motile cilium assembly	10	30.6×	1e-10
smoothened signaling pathway	12	22.9×	3e-11
dorsal/ventral pattern formation	5	22.2×	3e-04
cilium assembly	22	17.0×	9e-19
heart looping	5	14.1×	2e-03
kidney development	6	8.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

742 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	16
Uncertain significance	341
Likely benign	256
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1192529	NM_025103.4(IFT74):c.371_372del (p.Gln124fs)	Pathogenic
1300250	NM_025103.4(IFT74):c.92del (p.Leu31fs)	Pathogenic
1300251	NM_025103.4(IFT74):c.306-24A>G	Pathogenic
1373199	NM_025103.4(IFT74):c.253A>T (p.Lys85Ter)	Pathogenic
1416416	NM_025103.4(IFT74):c.592G>T (p.Glu198Ter)	Pathogenic
1452145	NM_025103.4(IFT74):c.1204C>T (p.Arg402Ter)	Pathogenic
1454954	NM_025103.4(IFT74):c.1024C>T (p.Gln342Ter)	Pathogenic
1455594	NM_025103.4(IFT74):c.1570del (p.Asn523_Ile524insTer)	Pathogenic
1686853	NM_025103.4(IFT74):c.975-2_975-1del	Pathogenic
1942091	NM_025103.4(IFT74):c.1129G>T (p.Glu377Ter)	Pathogenic
1970828	NM_025103.4(IFT74):c.509del (p.Met170fs)	Pathogenic
1974235	NM_025103.4(IFT74):c.64G>T (p.Gly22Ter)	Pathogenic
1974397	NM_025103.4(IFT74):c.69del (p.Arg23fs)	Pathogenic
1978627	NM_025103.4(IFT74):c.459C>A (p.Tyr153Ter)	Pathogenic
2030737	NM_025103.4(IFT74):c.686dup (p.Tyr230fs)	Pathogenic
2072074	NM_025103.4(IFT74):c.1383dup (p.Lys462Ter)	Pathogenic
2081790	NM_025103.4(IFT74):c.952G>T (p.Glu318Ter)	Pathogenic
2101851	NM_025103.4(IFT74):c.1399C>T (p.Gln467Ter)	Pathogenic
2101884	NM_025103.4(IFT74):c.1135_1136del (p.Lys379fs)	Pathogenic
2128526	NM_025103.4(IFT74):c.1478C>A (p.Ser493Ter)	Pathogenic
2164189	NM_025103.4(IFT74):c.106C>T (p.Arg36Ter)	Pathogenic
2178456	NM_025103.4(IFT74):c.1153C>T (p.Arg385Ter)	Pathogenic
2423692	NC_000009.11:g.(?26984235)(27009176_?)del	Pathogenic
2777137	NM_025103.4(IFT74):c.1141C>T (p.Gln381Ter)	Pathogenic
2824967	NM_025103.4(IFT74):c.771_774del (p.Lys258fs)	Pathogenic
2840034	NM_025103.4(IFT74):c.916_919del (p.Glu306fs)	Pathogenic
2905576	NM_025103.4(IFT74):c.915del (p.Glu306fs)	Pathogenic
2996783	NM_025103.4(IFT74):c.23C>A (p.Ser8Ter)	Pathogenic
3245301	NC_000009.11:g.(?26961966)(26962105_?)del	Pathogenic
3245302	NC_000009.11:g.(?26980549)(26980637_?)del	Pathogenic

SpliceAI

3648 predictions. Top by Δscore:

Variant	Effect	Δscore
9:26978125:TAGAT:T	acceptor_loss	1.0000
9:26978126:A:AG	acceptor_gain	1.0000
9:26978126:AG:A	acceptor_loss	1.0000
9:26978127:G:A	acceptor_loss	1.0000
9:26978127:G:GG	acceptor_gain	1.0000
9:26978127:GAT:G	acceptor_gain	1.0000
9:26984252:A:AG	acceptor_gain	1.0000
9:26984253:A:G	acceptor_gain	1.0000
9:26984254:TA:T	acceptor_loss	1.0000
9:26984255:A:AC	acceptor_loss	1.0000
9:26984255:A:AG	acceptor_gain	1.0000
9:26984256:G:GG	acceptor_gain	1.0000
9:26984256:G:GT	acceptor_loss	1.0000
9:26984256:GA:G	acceptor_gain	1.0000
9:26984256:GAA:G	acceptor_gain	1.0000
9:26984256:GAAGT:G	acceptor_gain	1.0000
9:26984353:GAG:G	donor_gain	1.0000
9:26984354:AGG:A	donor_loss	1.0000
9:26984356:G:GA	donor_loss	1.0000
9:26984356:G:GG	donor_gain	1.0000
9:26984357:T:G	donor_loss	1.0000
9:26988667:A:AG	acceptor_gain	1.0000
9:26988668:G:GA	acceptor_gain	1.0000
9:26990132:A:AG	acceptor_gain	1.0000
9:26990133:G:GG	acceptor_gain	1.0000
9:26990191:CAAGC:C	donor_gain	1.0000
9:26990193:AGC:A	donor_gain	1.0000
9:26990193:AGCGT:A	donor_loss	1.0000
9:26990194:GC:G	donor_gain	1.0000
9:26990194:GCG:G	donor_gain	1.0000

AlphaMissense

4026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:26984274:T:C	L108P	0.994
9:27016937:G:C	A274P	0.994
9:26984500:G:C	A136P	0.992
9:26984543:T:C	L150P	0.992
9:26980616:T:C	L101P	0.991
9:27016980:G:C	R288P	0.991
9:27060592:T:C	L542P	0.990
9:26990135:T:C	L176P	0.989
9:26980581:G:C	R89S	0.986
9:26980581:G:T	R89S	0.986
9:26984295:T:C	L115P	0.985
9:26980600:T:G	Y96D	0.983
9:26984512:G:C	A140P	0.983
9:27016959:T:C	L281P	0.983
9:26990179:T:C	F191L	0.982
9:26990181:T:A	F191L	0.982
9:26990181:T:G	F191L	0.982
9:26984545:G:C	A151P	0.980
9:26988682:T:C	L160P	0.978
9:26984556:C:A	N154K	0.976
9:26984556:C:G	N154K	0.976
9:26980580:G:C	R89T	0.974
9:26984501:C:A	A136D	0.974
9:26980592:A:T	D93V	0.973
9:26980591:G:C	D93H	0.971
9:27055633:T:C	L453P	0.971
9:26980592:A:C	D93A	0.964
9:27044769:T:C	L361P	0.964
9:26980613:T:C	L100P	0.963
9:27018671:G:C	A320P	0.963

dbSNP variants (sampled 300 via entrez): RS1000019385 (9:26979258 T>C), RS1000027251 (9:27042581 G>A,C), RS1000031772 (9:27010240 C>T), RS1000048152 (9:26973954 T>C), RS1000064759 (9:27048424 A>G), RS1000079198 (9:27047809 A>T), RS1000090928 (9:27010646 C>A), RS1000091135 (9:27048425 G>A,T), RS1000134336 (9:26952635 G>A), RS1000165785 (9:27025581 C>G,T), RS1000189768 (9:26999172 A>G), RS1000203073 (9:26954447 T>A,C,G), RS1000213541 (9:26988771 T>A,C,G), RS1000359871 (9:26987362 T>C), RS1000363999 (9:26958120 T>A,G)

Disease associations

OMIM: gene MIM:608040 | disease phenotypes: MIM:617119, MIM:209900, MIM:619582, MIM:213300, MIM:619585, MIM:208500, MIM:263520

GenCC curated gene-disease

Disease	Classification	Inheritance
Bardet-Biedl syndrome 22	Definitive	Autosomal recessive
ciliopathy	Strong	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive
spermatogenic failure 58	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy-IFT74	Definitive	AR

Mondo (12): Bardet-Biedl syndrome 22 (MONDO:0014926), Bardet-Biedl syndrome (MONDO:0015229), Joubert syndrome 40 (MONDO:0030462), Joubert syndrome (MONDO:0018772), spermatogenic failure 58 (MONDO:0030463), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), Jeune syndrome (MONDO:0018770), short-rib thoracic dysplasia 6 with or without polydactyly (MONDO:0009894), retinal disorder (MONDO:0005283), microcephaly (MONDO:0001149), ciliopathy (MONDO:0005308)

Orphanet (4): Bardet-Biedl syndrome (Orphanet:110), Isolated Joubert syndrome (Orphanet:475), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Jeune syndrome (Orphanet:474)

HPO phenotypes

147 total (30 of 147 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000100	Nephrotic syndrome
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000147	Polycystic ovaries
HP:0000163	Abnormal oral cavity morphology
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002337_137	Amyotrophic lateral sclerosis (sporadic)	2.000000e-06
GCST008477_7	Emphysema annual change measurement in smokers (adjusted lung density)	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C537571	Jeune syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment	5
trichostatin A	affects cotreatment, decreases expression	3
bisphenol F	increases expression, affects cotreatment	1
dicrotophos	decreases expression	1
bisphenol A	affects cotreatment, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
enzalutamide	affects expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Asbestos	affects expression	1
Caffeine	decreases phosphorylation	1
Dexamethasone	increases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Estradiol	affects expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Progesterone	increases expression	1
Selenium	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

112 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT00078091	Not specified	TERMINATED	Genetics and Clinical Characteristics of Bardet-Biedl Syndrome
NCT00213811	Not specified	COMPLETED	Bardet-Biedl Syndrome Study: Clinical and Genetic Epidemiology Study in Adults
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT02329210	Not specified	RECRUITING	Clinical Registry Investigating Bardet-Biedl Syndrome
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT04461444	Not specified	RECRUITING	COhort for Bardet-Bield Syndrome and Alström Syndrome for Translational Research Monocentric Interventional Study
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05183802	Not specified	APPROVED_FOR_MARKETING	An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
NCT05400278	Not specified	COMPLETED	Characterizing the Genotype and Phenotype in Adults With Bardet-Biedl Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06615011	Not specified	NOT_YET_RECRUITING	Bardet Beidle Syndrome in a Syrian Adolescent : a Rare Case Report
NCT07602803	Not specified	COMPLETED	The Effect of GLP1 Agonists on Weight Loss in BBS Cohort in the UK
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients