INTU

Summary

INTU (inturned planar cell polarity protein, HGNC:29239) is a protein-coding gene on chromosome 4q28.1, encoding Protein inturned (Q9ULD6). Plays a key role in ciliogenesis and embryonic development.

Predicted to enable phosphatidylinositol binding activity. Involved in embryonic digit morphogenesis; roof of mouth development; and tongue morphogenesis. Located in several cellular components, including ciliary basal body; cytosol; and motile cilium. Implicated in asphyxiating thoracic dystrophy and orofaciodigital syndrome XVII.

Source: NCBI Gene 27152 — RefSeq curated summary.

At a glance

• Gene–disease (curated): INTU-related skeletal ciliopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 474 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 63
• MANE Select transcript: NM_015693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29239
Approved symbol	INTU
Name	inturned planar cell polarity protein
Location	4q28.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1284, CPLANE4
Ensembl gene	ENSG00000164066
Ensembl biotype	protein_coding
OMIM	610621
Entrez	27152

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000335251, ENST00000503626, ENST00000503952, ENST00000504276, ENST00000504491, ENST00000506283, ENST00000510766, ENST00000512995, ENST00000885218, ENST00000885219, ENST00000917155, ENST00000917156, ENST00000917157, ENST00000917158, ENST00000917159, ENST00000943830, ENST00000943831

RefSeq mRNA: 1 — MANE Select: NM_015693 NM_015693

CCDS: CCDS34061

Canonical transcript exons

ENST00000335251 — 16 exons

Exon	Start	End
ENSE00001081025	127643521	127644056
ENSE00001081039	127656636	127656721
ENSE00001081042	127663381	127663584
ENSE00001125538	127674124	127674213
ENSE00001125545	127669036	127669154
ENSE00001348844	127687678	127687867
ENSE00002037197	127632957	127633180
ENSE00002085381	127716325	127726737
ENSE00003518202	127706487	127706969
ENSE00003534185	127708571	127708668
ENSE00003541449	127704228	127704290
ENSE00003545406	127705591	127705812
ENSE00003588227	127684409	127684486
ENSE00003591292	127713936	127714093
ENSE00003676839	127700010	127700063
ENSE00003690252	127710913	127711102

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 96.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8954 / max 341.5905, expressed in 1482 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49597	9.3482	1475
49596	0.3632	193
49598	0.1840	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.05	gold quality
bronchial epithelial cell	CL:0002328	92.85	gold quality
ventricular zone	UBERON:0003053	92.79	gold quality
bronchus	UBERON:0002185	91.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.14	gold quality
corpus callosum	UBERON:0002336	86.94	gold quality
ganglionic eminence	UBERON:0004023	86.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.52	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.87	gold quality
oviduct epithelium	UBERON:0004804	84.22	gold quality
calcaneal tendon	UBERON:0003701	84.01	gold quality
left ovary	UBERON:0002119	83.66	gold quality
adenohypophysis	UBERON:0002196	83.01	gold quality
tibial nerve	UBERON:0001323	82.50	gold quality
pituitary gland	UBERON:0000007	82.40	gold quality
right ovary	UBERON:0002118	82.29	gold quality
fallopian tube	UBERON:0003889	82.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.82	gold quality
ovary	UBERON:0000992	81.71	gold quality
tibia	UBERON:0000979	81.56	gold quality
popliteal artery	UBERON:0002250	80.79	gold quality
tibial artery	UBERON:0007610	80.78	gold quality
adrenal tissue	UBERON:0018303	80.77	gold quality
spinal cord	UBERON:0002240	80.74	gold quality
body of uterus	UBERON:0009853	80.53	gold quality
aorta	UBERON:0000947	79.30	gold quality
caput epididymis	UBERON:0004358	79.22	gold quality
mucosa of stomach	UBERON:0001199	78.98	gold quality
left lobe of thyroid gland	UBERON:0001120	78.80	gold quality
thyroid gland	UBERON:0002046	78.68	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	1847.46
E-MTAB-7037	yes	154.95
E-MTAB-5061	yes	13.27
E-MTAB-6678	no	1226.85
E-MTAB-10137	no	195.33
E-GEOD-83139	no	4.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

27 targeting INTU, 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-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-550A-3P	98.37	69.61	632
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-337-3P	97.90	69.37	1052
HSA-MIR-200C-5P	97.71	67.73	596

Literature-anchored findings (GeneRIF, showing 3)

• Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes. (PMID:33436679)
• Multifaceted investigation underlies diverse mechanisms contributing to the downregulation of Hedgehog pathway-associated genes INTU and IFT88 in lung adenocarcinoma and uterine corpus endometrial carcinoma. (PMID:36084949)
• Deficiency of the Planar Cell Polarity Protein Intu Delays Kidney Repair and Suppresses Renal Fibrosis after Acute Kidney Injury. (PMID:36586478)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	intu	ENSDARG00000077639
mus_musculus	Intu	ENSMUSG00000060798
rattus_norvegicus	Intu	ENSRNOG00000010556
drosophila_melanogaster	in	FBGN0001259

Protein

Protein identifiers

Protein inturned — Q9ULD6 (reviewed: Q9ULD6)

Alternative names: Inturned planar cell polarity effector homolog, PDZ domain-containing protein 6

All UniProt accessions (4): Q9ULD6, H0YA54, H0YAI1, J3QTA5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling. Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies. Required for recruitment of CPLANE2 to the mother centriole. Binds phosphatidylinositol 3-phosphate with highest affinity, followed by phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate.

Subunit / interactions. Component of the CPLANE (ciliogenesis and planar polarity effectors) complex, composed of INTU, FUZ and WDPCP. Interacts with CPLANE1. Interacts with NPHP4 and DAAM1; INTU is mediating the interaction between NPHP4 and DAAM1.

Subcellular location. Cytoplasm. Cell surface. Cytoskeleton. Cilium basal body. Microtubule organizing center. Centrosome. Centriole.

Disease relevance. Short-rib thoracic dysplasia 20 with polydactyly (SRTD20) [MIM:617925] A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. The disease is caused by variants affecting the gene represented in this entry. Orofaciodigital syndrome 17 (OFD17) [MIM:617926] A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD17 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Short-rib thoracic dysplasia 7/20 with polydactyly, digenic (SRTD7/20) [MIM:614091] A digenic form of short-rib thoracic dysplasia caused by double heterozygosity for a mutation in the WDR35 gene and a mutation in the INTU gene. Short-rib thoracic dysplasia is part of a group of ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. SRTD7/20 can be caused by co-occurrence of WDR35 variant p.Trp311Leu and INTU p.Gln276Ter. One such patient has been reported.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the inturned family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9ULD6-1	1	yes
Q9ULD6-2	2
Q9ULD6-3	3
Q9ULD6-4	4

RefSeq proteins (1): NP_056508* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR039151	INTU	Family
IPR043987	CCZ1/INTU/HSP4_longin_1	Domain
IPR043988	CCZ1/INTU_longin_2	Domain
IPR043989	CCZ1/INTU/HSP4_longin_3	Domain

Pfam: PF19031, PF19032, PF19033

UniProt features (53 total): strand 17, helix 16, splice variant 5, sequence variant 4, turn 3, region of interest 2, compositionally biased region 2, modified residue 2, chain 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9T1R	X-RAY DIFFRACTION	2.5
7Q3D	ELECTRON MICROSCOPY	3.35
9RS9	ELECTRON MICROSCOPY	3.4
9RS8	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULD6-F1	67.35	0.20

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): 670, 674

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-162582	Signal Transduction
R-HSA-5358351	Signaling by Hedgehog

MSigDB gene sets: 328 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELL_DIVISION, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_KERATINOCYTE_PROLIFERATION, GOCC_CELL_SURFACE, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_TONGUE_DEVELOPMENT, GOCC_MICROTUBULE_ORGANIZING_CENTER

GO Biological Process (24): establishment of planar polarity (GO:0001736), smoothened signaling pathway (GO:0007224), nervous system development (GO:0007399), regulation of smoothened signaling pathway (GO:0008589), negative regulation of keratinocyte proliferation (GO:0010839), vesicle-mediated transport (GO:0016192), spinal cord dorsal/ventral patterning (GO:0021513), neural tube development (GO:0021915), keratinocyte differentiation (GO:0030216), regulation of ossification (GO:0030278), hair follicle morphogenesis (GO:0031069), intraciliary transport (GO:0042073), embryonic digit morphogenesis (GO:0042733), tongue morphogenesis (GO:0043587), motile cilium assembly (GO:0044458), positive regulation of smoothened signaling pathway (GO:0045880), cell division (GO:0051301), negative regulation of cell division (GO:0051782), roof of mouth development (GO:0060021), limb development (GO:0060173), cilium assembly (GO:0060271), regulation of cilium assembly (GO:1902017), non-motile cilium assembly (GO:1905515), cell projection organization (GO:0030030)

GO Molecular Function (2): phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), centriole (GO:0005814), cytosol (GO:0005829), cilium (GO:0005929), cell surface (GO:0009986), motile cilium (GO:0031514), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cilium	4
smoothened signaling pathway	2
cellular process	2
microtubule organizing center	2
intracellular membraneless organelle	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
cell surface receptor signaling pathway	1
system development	1
regulation of signal transduction	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
transport	1
dorsal/ventral pattern formation	1
spinal cord patterning	1
nervous system development	1
tube development	1
chordate embryonic development	1
epithelium development	1
epidermal cell differentiation	1
skin development	1
ossification	1
regulation of multicellular organismal process	1
hair follicle development	1
anatomical structure morphogenesis	1
hair cycle process	1
epidermis morphogenesis	1
transport along microtubule	1
cilium organization	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
tongue development	1
sensory organ morphogenesis	1
cilium assembly	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
negative regulation of cellular process	1
cell division	1

Protein interactions and networks

STRING

2817 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INTU	FUZ	Q9BT04	995
INTU	CPLANE2	Q9BU20	918
INTU	WDPCP	O95876	893
INTU	IFT43	Q96FT9	672
INTU	VANGL2	Q9ULK5	664
INTU	CELSR1	Q9NYQ6	605
INTU	NPHP4	O75161	594
INTU	PRICKLE3	O43900	577
INTU	PRICKLE1	Q96MT3	572
INTU	PRICKLE4	Q2TBC4	570
INTU	PRICKLE2	Q7Z3G6	565
INTU	MFSD8	Q8NHS3	542
INTU	RAB23	Q9ULC3	538
INTU	WDR19	Q8NEZ3	520
INTU	DYNLT2B	Q8WW35	519

IntAct

59 interactions, top by confidence:

A	B	Type	Score
FUZ	INTU	psi-mi:“MI:0915”(physical association)	0.660
INTU	E6	psi-mi:“MI:0407”(direct interaction)	0.440
E6	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
INTU	PBK	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
ABCC4	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
INTU	CYSLTR2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
KIR3DL3	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K2	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
RALBP1	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
RASSF6	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
TJP2	INTU	psi-mi:“MI:0407”(direct interaction)	0.440
INTU	NPHP4	psi-mi:“MI:0915”(physical association)	0.400
INTU	DAAM1	psi-mi:“MI:0915”(physical association)	0.400
NPHP4	INTU	psi-mi:“MI:0915”(physical association)	0.400
DAAM1	NPHP4	psi-mi:“MI:0915”(physical association)	0.400
CFTR	INTU	psi-mi:“MI:0915”(physical association)	0.370
CPLANE2	FUZ	psi-mi:“MI:0914”(association)	0.350
INTU	EED	psi-mi:“MI:0914”(association)	0.350
FUZ	UBB	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): INTU (Affinity Capture-MS), INTU (Affinity Capture-MS), INTU (Affinity Capture-MS), INTU (Affinity Capture-MS), SUZ12 (Affinity Capture-MS), APPBP2 (Affinity Capture-MS), EED (Affinity Capture-MS), EME1 (Affinity Capture-MS), RPTOR (Affinity Capture-MS), FNTB (Affinity Capture-MS), AP2M1 (Affinity Capture-MS), NCAPG (Affinity Capture-MS), TOP2A (Affinity Capture-MS), UBB (Affinity Capture-MS), MCRS1 (Affinity Capture-MS)

ESM2 similar proteins: A1L3F5, A2RT67, A2RUS2, A4D1U4, B1H2P5, D3ZXK7, D4ACE5, E7F240, F1MDL2, F1QEB7, F1R7R1, H2LP95, O75161, O94967, P48553, P59240, Q059U7, Q0PGW2, Q28DH9, Q3TLI0, Q3U0J8, Q3UHG7, Q4R5A4, Q5FVM6, Q5JPI3, Q5M7Q1, Q5M9F0, Q5R989, Q5RC14, Q5XPI3, Q5XPI4, Q5ZJK1, Q6DDX8, Q6NXD8, Q6VNB8, Q7TSG1, Q80TA6, Q8CGF6, Q8IY22, Q8IZQ1

Diamond homologs: D4ACE5, E7FCN8, F1MDL2, F6U5F9, Q059U7, Q2I0E5, Q9ULD6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
INTU	“form complex”	“CPLANE complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 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
Vif-mediated degradation of APOBEC3G	9	55.7×	8e-12
AUF1 (hnRNP D0) binds and destabilizes mRNA	9	54.5×	8e-12
Regulation of activated PAK-2p34 by proteasome mediated degradation	8	54.4×	5e-11
Vpu mediated degradation of CD4	8	51.8×	6e-11
Autodegradation of the E3 ubiquitin ligase COP1	8	51.8×	6e-11
Ubiquitin-dependent degradation of Cyclin D	8	51.8×	6e-11
Degradation of AXIN	8	48.4×	8e-11
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	8	48.4×	8e-11

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	5	17.2×	2e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	8	8.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	283
Likely benign	114
Benign	43

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1069575	NC_000004.11:g.(?128544537)(129131208_?)del	Pathogenic
1694472	NM_015693.4(INTU):c.2358_2359dup (p.Asn787fs)	Pathogenic
3255222	NM_015693.4(INTU):c.576del (p.Lys193fs)	Pathogenic
1341890	NM_015693.4(INTU):c.1305dup (p.Asn436Ter)	Likely pathogenic
504481	NM_015693.4(INTU):c.1063G>T (p.Glu355Ter)	Likely pathogenic
504482	NM_015693.4(INTU):c.1499A>C (p.Glu500Ala)	Likely pathogenic

SpliceAI

3801 predictions. Top by Δscore:

Variant	Effect	Δscore
4:127633173:GATTA:G	donor_gain	1.0000
4:127633179:GA:G	donor_gain	1.0000
4:127633181:G:GG	donor_gain	1.0000
4:127643517:A:AG	acceptor_gain	1.0000
4:127643517:ATAGT:A	acceptor_gain	1.0000
4:127643518:T:G	acceptor_gain	1.0000
4:127643519:A:AG	acceptor_gain	1.0000
4:127643519:AGT:A	acceptor_gain	1.0000
4:127643520:G:GA	acceptor_gain	1.0000
4:127643520:GT:G	acceptor_gain	1.0000
4:127643520:GTG:G	acceptor_gain	1.0000
4:127643520:GTGAT:G	acceptor_gain	1.0000
4:127656623:ATTCT:A	acceptor_gain	1.0000
4:127656627:T:TA	acceptor_gain	1.0000
4:127656628:G:A	acceptor_gain	1.0000
4:127656630:TTTCA:T	acceptor_loss	1.0000
4:127656631:TTCAG:T	acceptor_loss	1.0000
4:127656632:TCAG:T	acceptor_loss	1.0000
4:127656633:CAGGT:C	acceptor_loss	1.0000
4:127656634:A:AG	acceptor_gain	1.0000
4:127656634:AG:A	acceptor_gain	1.0000
4:127656634:AGGT:A	acceptor_gain	1.0000
4:127656635:G:GT	acceptor_gain	1.0000
4:127656635:GG:G	acceptor_gain	1.0000
4:127656635:GGT:G	acceptor_gain	1.0000
4:127656635:GGTG:G	acceptor_gain	1.0000
4:127656635:GGTGA:G	acceptor_gain	1.0000
4:127656718:GCAG:G	donor_gain	1.0000
4:127656720:AGGTA:A	donor_loss	1.0000
4:127656721:GGTAT:G	donor_loss	1.0000

AlphaMissense

6181 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:127656669:T:A	V239D	0.999
4:127644003:T:A	V210D	0.998
4:127656650:G:C	A233P	0.998
4:127656645:T:A	L231H	0.997
4:127656696:T:C	L248P	0.996
4:127663388:T:C	L259P	0.996
4:127705708:T:A	W562R	0.996
4:127705708:T:C	W562R	0.996
4:127716367:T:G	C920W	0.995
4:127643537:T:A	W55R	0.994
4:127643537:T:C	W55R	0.994
4:127656645:T:G	L231R	0.994
4:127710942:T:C	F800S	0.994
4:127714080:T:G	Y902D	0.994
4:127716363:T:A	V919D	0.994
4:127716365:T:C	C920R	0.994
4:127644030:C:A	A219D	0.993
4:127656696:T:A	L248Q	0.993
4:127656654:T:A	V234E	0.992
4:127663547:T:C	L312P	0.992
4:127669112:T:C	L350P	0.992
4:127656696:T:G	L248R	0.991
4:127714092:G:T	G906W	0.991
4:127656645:T:C	L231P	0.990
4:127656693:T:A	V247D	0.988
4:127716359:T:G	Y918D	0.988
4:127716366:G:A	C920Y	0.988
4:127643568:T:C	L65P	0.987
4:127705792:T:C	F590L	0.987
4:127705794:T:A	F590L	0.987

dbSNP variants (sampled 300 via entrez): RS1000026039 (4:127689527 G>A,C), RS1000044106 (4:127621247 T>A), RS1000046096 (4:127672646 G>A), RS1000104708 (4:127683929 C>T), RS1000165593 (4:127666454 A>G), RS1000168790 (4:127684130 T>A,C), RS1000253422 (4:127683557 C>G,T), RS1000278593 (4:127621576 A>C), RS1000279875 (4:127723239 G>A), RS1000288651 (4:127709459 A>G), RS1000300776 (4:127656176 C>T), RS1000328383 (4:127691064 T>C), RS1000371500 (4:127683743 A>G), RS1000422839 (4:127643947 G>A), RS1000452410 (4:127658870 A>C)

Disease associations

OMIM: gene MIM:610621 | disease phenotypes: MIM:610951, MIM:617926, MIM:617925, MIM:208500, MIM:252100, MIM:256100

GenCC curated gene-disease

Disease	Classification	Inheritance
orofaciodigital syndrome 17	Strong	Autosomal recessive
short-rib thoracic dysplasia 20 with polydactyly	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
INTU-related skeletal ciliopathy	Definitive	AR

Mondo (8): neuronal ceroid lipofuscinosis 7 (MONDO:0012588), orofaciodigital syndrome 17 (MONDO:0033375), short-rib thoracic dysplasia 20 with polydactyly (MONDO:0044328), Jeune syndrome (MONDO:0018770), short rib-polydactyly syndrome (MONDO:0015461), short-rib thoracic dysplasia 7/20 with polydactyly, digenic (MONDO:0800356), orofaciodigital syndrome type II (MONDO:0009642), nephronophthisis (MONDO:0019005)

Orphanet (6): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN7 disease (Orphanet:228366), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome (Orphanet:1505), Orofaciodigital syndrome type 2 (Orphanet:2751), Nephronophthisis (Orphanet:655)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000089	Renal hypoplasia
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000248	Brachycephaly
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000448	Prominent nose
HP:0000470	Short neck
HP:0000568	Microphthalmia
HP:0000695	Natal tooth
HP:0000750	Delayed speech and language development
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000888	Horizontal ribs
HP:0000895	Lateral clavicle hook
HP:0001153	Septate vagina
HP:0001636	Tetralogy of Fallot
HP:0001674	Complete atrioventricular canal defect
HP:0002007	Frontal bossing
HP:0002023	Anal atresia
HP:0002089	Pulmonary hypoplasia
HP:0002119	Ventriculomegaly
HP:0002162	Low posterior hairline

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004602_29	Mean corpuscular volume	5.000000e-09
GCST004630_143	Mean corpuscular hemoglobin	3.000000e-09
GCST008661_2	Lung function in heavy smokers (high FEV1 vs average FEV1)	3.000000e-08
GCST009464_22	Facial morphology	3.000000e-10
GCST009464_27	Facial morphology	2.000000e-09
GCST009464_5	Facial morphology	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004314	forced expiratory volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D012779	Short Rib-Polydactyly Syndrome	C05.116.099.708.857; C05.660.585.600.750; C16.131.077.850; C16.131.621.585.600.750
C563989	Ceroid Lipofuscinosis, Neuronal, 7 (supp.)
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Nickel	decreases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, decreases methylation, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects expression	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
abrine	increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Coal	decreases expression, increases abundance	1
Copper	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Manganese	increases abundance, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Naled	affects expression	1
Quercetin	decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression, increases abundance	1
Testosterone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04737460	PHASE1	ACTIVE_NOT_RECRUITING	Study for the Treatment for CLN7 Disease
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT00948376	Not specified	COMPLETED	Natural History of Asphyxiating Thoracic Dystrophy (DTJ)
NCT04143841	Not specified	TERMINATED	Viveye Ocular Magnetic Neurostimulation System (OMNS) for the Management of Severe Dry Eye Disease
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT01022957	Not specified	COMPLETED	Nephronophthisis : Clinical and Genetic Study
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06648044	Not specified	RECRUITING	Research of Therapeutic Targets in the Frame of Nephronophthisis and Renal Associated Ciliopathies