IFT122

Summary

IFT122 (intraflagellar transport 122, HGNC:13556) is a protein-coding gene on chromosome 3q21.3-q22.1, encoding Intraflagellar transport protein 122 homolog (Q9HBG6). As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is required in ciliogenesis and ciliary protein trafficking.

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 55764 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cranioectodermal dysplasia 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 1,093 total — 43 pathogenic, 39 likely-pathogenic
• Phenotypes (HPO): 79
• MANE Select transcript: NM_052989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13556
Approved symbol	IFT122
Name	intraflagellar transport 122
Location	3q21.3-q22.1
Locus type	gene with protein product
Status	Approved
Aliases	WDR140, WDR10p, SPG, FAP80, CFAP80
Ensembl gene	ENSG00000163913
Ensembl biotype	protein_coding
OMIM	606045
Entrez	55764

Gene structure

Transcript identifiers

Ensembl transcripts: 129 — 60 protein_coding, 34 nonsense_mediated_decay, 27 retained_intron, 8 protein_coding_CDS_not_defined

ENST00000296266, ENST00000347300, ENST00000348417, ENST00000349441, ENST00000431818, ENST00000440957, ENST00000448668, ENST00000502304, ENST00000502456, ENST00000504021, ENST00000504444, ENST00000504653, ENST00000506507, ENST00000507221, ENST00000507564, ENST00000508654, ENST00000509195, ENST00000509522, ENST00000509815, ENST00000510524, ENST00000511425, ENST00000511498, ENST00000512157, ENST00000512220, ENST00000512814, ENST00000513190, ENST00000513891, ENST00000513932, ENST00000514081, ENST00000515783, ENST00000685087, ENST00000685122, ENST00000685189, ENST00000685282, ENST00000685447, ENST00000685512, ENST00000685621, ENST00000685811, ENST00000685921, ENST00000685939, ENST00000686375, ENST00000686473, ENST00000686531, ENST00000686614, ENST00000686830, ENST00000687377, ENST00000687398, ENST00000687461, ENST00000687645, ENST00000687766, ENST00000687776, ENST00000687791, ENST00000687845, ENST00000687864, ENST00000688020, ENST00000688129, ENST00000688266, ENST00000688392, ENST00000688504, ENST00000688527, ENST00000688657, ENST00000688664, ENST00000688765, ENST00000688970, ENST00000689005, ENST00000689313, ENST00000689332, ENST00000689384, ENST00000689492, ENST00000689643, ENST00000689796, ENST00000689801, ENST00000689819, ENST00000689871, ENST00000689884, ENST00000690209, ENST00000690617, ENST00000690657, ENST00000690663, ENST00000690677, ENST00000690723, ENST00000690800, ENST00000690862, ENST00000691148, ENST00000691360, ENST00000691583, ENST00000691641, ENST00000691705, ENST00000691733, ENST00000691770, ENST00000691964, ENST00000692228, ENST00000692242, ENST00000692321, ENST00000692391, ENST00000692508, ENST00000692728, ENST00000692901, ENST00000692929, ENST00000692985, ENST00000693114, ENST00000693129, ENST00000693162, ENST00000693233, ENST00000693489, ENST00000693588, ENST00000693654, ENST00000875675, ENST00000875676, ENST00000875677, ENST00000875678, ENST00000914789, ENST00000957287, ENST00000957288, ENST00000957289, ENST00000957290, ENST00000957291, ENST00000957292, ENST00000957293, ENST00000957294, ENST00000957295, ENST00000957296, ENST00000957297, ENST00000957298, ENST00000957299, ENST00000957300, ENST00000957301, ENST00000957302, ENST00000957303

RefSeq mRNA: 14 — MANE Select: NM_052989 NM_001280541, NM_001280545, NM_001280546, NM_001410808, NM_001410809, NM_001410810, NM_001410811, NM_001410813, NM_001410815, NM_001410817, NM_018262, NM_052985, NM_052989, NM_052990

CCDS: CCDS3059, CCDS3060, CCDS3061, CCDS3062, CCDS63770, CCDS93372, CCDS93374, CCDS93375, CCDS93376, CCDS93377, CCDS93379, CCDS93380

Canonical transcript exons

ENST00000348417 — 30 exons

Exon	Start	End
ENSE00002058410	129440224	129440371
ENSE00003461334	129519107	129519186
ENSE00003463273	129476663	129476801
ENSE00003465249	129463560	129463626
ENSE00003465682	129479785	129479922
ENSE00003478831	129512312	129512412
ENSE00003485614	129517469	129517594
ENSE00003500226	129466890	129467066
ENSE00003503756	129483485	129483682
ENSE00003511159	129492141	129492194
ENSE00003511691	129514389	129514554
ENSE00003525965	129458599	129458677
ENSE00003530126	129478016	129478218
ENSE00003534873	129502711	129502882
ENSE00003535678	129449871	129449937
ENSE00003573274	129469342	129469417
ENSE00003576398	129499902	129500068
ENSE00003589828	129461228	129461304
ENSE00003607522	129476315	129476506
ENSE00003609417	129464635	129464781
ENSE00003618681	129495446	129495607
ENSE00003629659	129507668	129507762
ENSE00003634655	129506409	129506549
ENSE00003649503	129519568	129519732
ENSE00003665287	129451914	129451998
ENSE00003670257	129515488	129515599
ENSE00003674843	129481530	129481694
ENSE00003681030	129488257	129488397
ENSE00003789065	129504319	129504421
ENSE00003899218	129520176	129520507

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.3901 / max 531.3781, expressed in 1816 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38529	11.9051	1778
38527	4.1672	1463
38530	0.8377	313
38528	0.2690	112
38531	0.2112	145

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	97.84	gold quality
left testis	UBERON:0004533	97.83	gold quality
right uterine tube	UBERON:0001302	96.44	gold quality
testis	UBERON:0000473	96.32	gold quality
sural nerve	UBERON:0015488	94.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.13	gold quality
left ovary	UBERON:0002119	93.41	gold quality
calcaneal tendon	UBERON:0003701	92.89	gold quality
adult organism	UBERON:0007023	92.85	gold quality
pituitary gland	UBERON:0000007	92.14	gold quality
adenohypophysis	UBERON:0002196	92.06	gold quality
sperm	CL:0000019	92.02	gold quality
right ovary	UBERON:0002118	92.02	gold quality
right lobe of thyroid gland	UBERON:0001119	92.01	gold quality
male germ cell	CL:0000015	91.72	gold quality
metanephros cortex	UBERON:0010533	91.63	gold quality
endocervix	UBERON:0000458	91.56	gold quality
tibial nerve	UBERON:0001323	91.53	gold quality
left lobe of thyroid gland	UBERON:0001120	91.17	gold quality
mucosa of stomach	UBERON:0001199	91.07	gold quality
epithelium of bronchus	UBERON:0002031	90.91	gold quality
thyroid gland	UBERON:0002046	90.91	gold quality
body of pancreas	UBERON:0001150	90.68	gold quality
body of uterus	UBERON:0009853	90.61	gold quality
ovary	UBERON:0000992	90.55	gold quality
bronchus	UBERON:0002185	90.51	gold quality
right lung	UBERON:0002167	90.37	gold quality
right frontal lobe	UBERON:0002810	90.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.29	gold quality
bronchial epithelial cell	CL:0002328	90.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting IFT122, 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-1236-3P	99.94	68.04	1695
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-5590-5P	98.81	68.78	969
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-4486	96.96	60.61	931

Literature-anchored findings (GeneRIF, showing 8)

• we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with Sensenbrenner syndrome (PMID:20493458)
• this study was able to find causative IFT122 mutations in a non-consanguineous family with recurrent abortions. (PMID:23826986)
• The three patients had different, novel, compound heterozygous mutations in IFT122. Consequently, we compared these three patients to those previously described with IFT122 mutations. Thus, our report serves to add 6 novel mutations to the IFT122 mutation spectrum and to contribute to the IFT122-related clinical characterization. (PMID:26792575)
• Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement. (PMID:28370949)
• All the nine probands with syndromic craniosynostosis were found to carry the possibly causative variants, among which three variants including two missense mutations in IFT122 gene, in SMC1A gene and a frameshift mutation in TWIST1 gene have never been reported in patients before. (PMID:29037998)
• This study demonstrated that the mutation in SPG 7 gene caused autosomal recessive hereditary spastic paraparesis. (PMID:29057857)
• IFT122 mutations associated with cranioectodermal dysplasia 1 cause defects in ciliary protein trafficking, but not ciliogenesis when expressed in cells lacking endogenous IFT122 (IFT122 KO). (PMID:29220510)
• The C11ORF74, interacts with the IFT-A complex via the IFT122 subunit and is accumulated at the distal tip in the absence of an IFT-A subunit IFT139, suggesting that at least a fraction of C11ORF74 molecules can be transported towards the ciliary tip by associating with the IFT-A complex, although its majority might be out of cilia at steady state. (PMID:30476139)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ift122	ENSMUSG00000030323
rattus_norvegicus	Ift122	ENSRNOG00000010952
drosophila_melanogaster	Oseg1	FBGN0265102
caenorhabditis_elegans		WBGENE00000906

Protein

Protein identifiers

Intraflagellar transport protein 122 homolog — Q9HBG6 (reviewed: Q9HBG6)

Alternative names: WD repeat-containing protein 10, WD repeat-containing protein 140

All UniProt accessions (60): A0A8C8L0T3, A0A8I5KNX7, A0A8I5KP73, A0A8I5KPB4, A0A8I5KQ16, A0A8I5KQF6, A0A8I5KR03, A0A8I5KR07, A0A8I5KRP5, A0A8I5KS77, A0A8I5KS91, A0A8I5KSG5, A0A8I5KSN5, A0A8I5KSQ0, A0A8I5KSV0, A0A8I5KT04, A0A8I5KT76, A0A8I5KT78, A0A8I5KTI2, A0A8I5KTL4, A0A8I5KTT9, A0A8I5KUK8, A0A8I5KUU2, A0A8I5KUV2, A0A8I5KUY3, A0A8I5KV39, Q9HBG6, A0A8I5KVC7, A0A8I5KW25, A0A8I5KW32, A0A8I5KWK4, A0A8I5KX14, A0A8I5KX44, A0A8I5KXA7, A0A8I5KXC8, A0A8I5KXT5, A0A8I5KYB6, A0A8I5KYR0, A0A8I5KYT5, A0A8I5KYX1, A0A8I5KZ03, A0A8I5QJE0, A0A8I5QJX4, A0A8I5QKJ5, A0A8I5QKR8, A0A8I5QKV2, A0A8I5QKV6, A0A8I5QKX8, A0A8I5QKY6, A0A8I5QL12, A0A8I5QL25, A0A8J9A3C6, D6RAF7, D6RIB5, H0Y978, H0Y9I6, H0Y9Q2, H0Y9Y9, H0YAG6, H0YAG9

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is required in ciliogenesis and ciliary protein trafficking. Involved in cilia formation during neuronal patterning. Acts as a negative regulator of Shh signaling. Required to recruit TULP3 to primary cilia.

Subunit / interactions. Component of the IFT complex A (IFT-A) complex. IFT-A complex is divided into a core subcomplex composed of IFT122:IFT140:WDR19 which is associated with TULP3 and a peripheral subcomplex composed of IFT43:WDR35:TTC21B. Interacts with IFT43:WDR35; the interaction connects the 2 IFT-A subcomplexes. Interacts with IFTAP; the interaction associates IFTAP with IFT-A complex.

Subcellular location. Cell projection. Cilium. Cytoplasm. Cytoskeleton. Cilium basal body.

Tissue specificity. Expressed in many tissues. Predominant expression in testis and pituitary.

Disease relevance. Cranioectodermal dysplasia 1 (CED1) [MIM:218330] A disorder characterized by craniofacial, skeletal and ectodermal abnormalities. Clinical features include dolichocephaly (with or without sagittal suture synostosis), scaphocephaly, short stature, limb shortening, short ribs, narrow chest, brachydactyly, renal failure and hepatic fibrosis, small and abnormally shaped teeth, sparse hair, skin laxity and abnormal nails. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Forms the trimeric core subcomplex IFT122:IFT140:WDR19 via the C-terminal region, whereas it interacts with IFT43:WDR35 via the N-terminal region containing the WD repeats.

Isoforms (10)

UniProt ID	Names	Canonical?
Q9HBG6-1	1	yes
Q9HBG6-3	3
Q9HBG6-4	4
Q9HBG6-5	5
Q9HBG6-6	6
Q9HBG6-7	7
Q9HBG6-8	8
Q9HBG6-9	9
Q9HBG6-10	10
Q9HBG6-11	11

RefSeq proteins (14): NP_001267470, NP_001267474, NP_001267475, NP_001397737, NP_001397738, NP_001397739, NP_001397740, NP_001397742, NP_001397744, NP_001397746, NP_060732, NP_443711, NP_443715, NP_443716 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039857	Ift122/121	Family
IPR056152	Beta-prop_IFT122_2nd	Domain
IPR056153	IFT122/SMU1_beta-prop	Domain
IPR056838	Zn_ribbon_IFT122	Domain
IPR057411	TPR_IFT122	Domain

Pfam: PF23377, PF23381, PF25143, PF25144, PF25295

UniProt features (150 total): strand 62, helix 37, turn 14, splice variant 10, sequence conflict 9, sequence variant 8, repeat 7, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8BBE	ELECTRON MICROSCOPY	3.5
8BBG	ELECTRON MICROSCOPY	3.5
8FGW	ELECTRON MICROSCOPY	3.7
8FH3	ELECTRON MICROSCOPY	4.3
8BBF	ELECTRON MICROSCOPY	8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBG6-F1	82.91	0.40

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620924	Intraflagellar transport

MSigDB gene sets: 373 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_FORELIMB_MORPHOGENESIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_HEART_TUBE_DEVELOPMENT

GO Biological Process (22): neural tube closure (GO:0001843), embryonic body morphogenesis (GO:0010172), spinal cord dorsal/ventral patterning (GO:0021513), embryonic heart tube development (GO:0035050), embryonic forelimb morphogenesis (GO:0035115), intracellular signal transduction (GO:0035556), intraciliary anterograde transport (GO:0035720), intraciliary retrograde transport (GO:0035721), intraciliary transport (GO:0042073), negative regulation of smoothened signaling pathway (GO:0045879), camera-type eye morphogenesis (GO:0048593), limb development (GO:0060173), cilium assembly (GO:0060271), embryonic heart tube left/right pattern formation (GO:0060971), protein localization to cilium (GO:0061512), establishment of protein localization to organelle (GO:0072594), non-motile cilium assembly (GO:1905515), nervous system development (GO:0007399), heart development (GO:0007507), regulation of smoothened signaling pathway (GO:0008589), cell projection organization (GO:0030030), establishment of protein localization (GO:0045184)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (17): nucleoplasm (GO:0005654), cytosol (GO:0005829), cilium (GO:0005929), membrane (GO:0016020), intraciliary transport particle A (GO:0030991), nuclear membrane (GO:0031965), photoreceptor connecting cilium (GO:0032391), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), ciliary tip (GO:0097542), non-motile cilium (GO:0097730), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	9
cilium	6
intracellular anatomical structure	2
intraciliary transport	2
cilium organization	2
smoothened signaling pathway	2
intraciliary transport particle	2
sperm flagellum	2
primary neural tube formation	1
tube closure	1
body morphogenesis	1
embryonic morphogenesis	1
dorsal/ventral pattern formation	1
spinal cord patterning	1
heart development	1
tube development	1
embryonic organ development	1
epithelium development	1
embryonic limb morphogenesis	1
forelimb morphogenesis	1
signal transduction	1
transport along microtubule	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
camera-type eye development	1
eye morphogenesis	1
appendage development	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
embryonic heart tube development	1
left/right pattern formation	1
protein localization to organelle	1
establishment of protein localization	1
cilium assembly	1
system development	1

Protein interactions and networks

STRING

2315 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFT122	IFT140	Q96RY7	997
IFT122	IFT43	Q96FT9	996
IFT122	TTC21B	Q7Z4L5	995
IFT122	WDR19	Q8NEZ3	992
IFT122	GULP1	Q9UBP9	990
IFT122	WDR35	Q9P2L0	986
IFT122	MEGF10	Q96KG7	858
IFT122	IFT88	Q13099	852
IFT122	SNX1	Q13596	842
IFT122	SNX6	Q9UNH7	821
IFT122	IFT172	Q9UG01	811
IFT122	IFT52	Q9Y366	806
IFT122	IFT80	Q9P2H3	795
IFT122	ELMO2	Q96JJ3	794
IFT122	TULP3	O75386	784

IntAct

102 interactions, top by confidence:

A	B	Type	Score
WDR19	TULP3	psi-mi:“MI:0914”(association)	0.860
TULP3	WDR19	psi-mi:“MI:0915”(physical association)	0.860
TULP3	WDR19	psi-mi:“MI:0914”(association)	0.860
IFT122	WDR19	psi-mi:“MI:0914”(association)	0.800
IFT122	WDR19	psi-mi:“MI:0915”(physical association)	0.800
WDR19	IFT122	psi-mi:“MI:0915”(physical association)	0.800
IFT122	IFT43	psi-mi:“MI:0915”(physical association)	0.800
TULP3	FOXK2	psi-mi:“MI:0914”(association)	0.790
IFT43	TULP3	psi-mi:“MI:0914”(association)	0.790
IFT140	WDR19	psi-mi:“MI:0915”(physical association)	0.780
IFT140	WDR19	psi-mi:“MI:0914”(association)	0.780
TTC21B	IFT43	psi-mi:“MI:0915”(physical association)	0.770
TTC21B	IFT43	psi-mi:“MI:0914”(association)	0.770
IFT122	TTC21B	psi-mi:“MI:0915”(physical association)	0.700
IFTAP	PLK1	psi-mi:“MI:0914”(association)	0.640
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
ORF	EIF3D	psi-mi:“MI:0914”(association)	0.560
IFT122	ORF	psi-mi:“MI:0915”(physical association)	0.560
IFT43	TTC21B	psi-mi:“MI:0914”(association)	0.530
IARS2	GAK	psi-mi:“MI:0914”(association)	0.530
IFT122	DNAJA2	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
DNAJA1	DNAJA2	psi-mi:“MI:0914”(association)	0.530
TULP3	HSPG2	psi-mi:“MI:0914”(association)	0.530
IFTAP	WDR19	psi-mi:“MI:0914”(association)	0.530

BioGRID (102): IFT122 (Affinity Capture-MS), IFT140 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), SDF4 (Affinity Capture-MS), WDR19 (Affinity Capture-MS), IFT43 (Affinity Capture-MS), PIH1D1 (Affinity Capture-MS), IFT122 (Affinity Capture-MS), IFT122 (Affinity Capture-MS), IFT122 (Affinity Capture-MS), IFT122 (Affinity Capture-MS), IFT122 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR19 (Affinity Capture-MS), IFT122 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8EXB5, A4QNE6, A8WGF4, C1BK83, O35142, O43684, O55029, P35605, P35606, Q17QU5, Q1JP79, Q1JQB2, Q29RH4, Q29RZ9, Q3UGF1, Q4FZW5, Q4R4I8, Q561Y0, Q5I0B4, Q5M7F6, Q5MNZ6, Q5R664, Q5RB58, Q5U4Y8, Q5VQ78, Q6GNF1, Q6NWV3, Q6PA72, Q6TGU2, Q803V5, Q8AVT9, Q8BGF3, Q8IWZ6, Q8K2G4, Q8L828, Q8NEZ3, Q8VE80, Q92747, Q96J01, Q96MX6

Diamond homologs: A8WGF4, G5EFW7, Q54U63, Q6NWV3, Q6NYH1, Q9HBG6, A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A8QCE4, A8XJZ8, A8XXC7, B0G126, D2H5P6, D4A8G9, E1BLZ4, E9Q4P1, O14964, O88387, O95170, P34657, P52734, P98174, Q0CJV3, Q0P4S0, Q0U4Z8, Q0V8S0, Q11176, Q13615, Q17AN2, Q18964, Q22712, Q2GS33, Q2KIY3, Q3TB82, Q4P7Q1, Q4WHN8, Q54CH1, Q54TC3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IFT122	“form complex”	“ITF complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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	7	22.6×	7e-06
Hedgehog ‘off’ state	6	17.3×	2e-04
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	15.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
intraciliary retrograde transport	5	64.6×	2e-06
protein localization to cilium	7	32.3×	1e-06
protein folding	10	11.9×	2e-06
cilium assembly	8	6.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1093 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	39
Uncertain significance	503
Likely benign	324
Benign	64

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179190	NM_052989.3(IFT122):c.2285del (p.Lys762fs)	Pathogenic
1323103	NM_052989.3(IFT122):c.3426_3430del (p.Ser1143fs)	Pathogenic
1329086	NM_052989.3(IFT122):c.3726A>G (p.Ter1242Trp)	Pathogenic
1368335	NM_052989.3(IFT122):c.2668C>T (p.Arg890Ter)	Pathogenic
1435502	NM_052989.3(IFT122):c.1432dup (p.Val478fs)	Pathogenic
1456968	NC_000003.11:g.(?129159174)(129214470_?)del	Pathogenic
191185	NM_052989.3(IFT122):c.2375+2T>C	Pathogenic
1933293	NM_052989.3(IFT122):c.3013C>T (p.Gln1005Ter)	Pathogenic
1995864	NM_052989.3(IFT122):c.384del (p.Lys128fs)	Pathogenic
2009853	NM_052989.3(IFT122):c.3180C>A (p.Cys1060Ter)	Pathogenic
2017547	NM_052989.3(IFT122):c.273-374_273-369dup	Pathogenic
2033213	NM_052989.3(IFT122):c.347_348del (p.Phe116fs)	Pathogenic
2038023	NM_052989.3(IFT122):c.273-341dup	Pathogenic
2094522	NM_052989.3(IFT122):c.3563del (p.Pro1188fs)	Pathogenic
2156861	NM_052989.3(IFT122):c.1198C>T (p.Arg400Ter)	Pathogenic
2203430	NM_052989.3(IFT122):c.3076_3080delinsGTA (p.Tyr1026fs)	Pathogenic
2693250	NM_052989.3(IFT122):c.2705_2706del (p.Thr902fs)	Pathogenic
2757396	NM_052989.3(IFT122):c.273-257C>A	Pathogenic
2770134	NM_052989.3(IFT122):c.443_449dup (p.Met151fs)	Pathogenic
2800797	NM_052989.3(IFT122):c.3575G>A (p.Trp1192Ter)	Pathogenic
280161	NM_052989.3(IFT122):c.2311_2312del (p.Tyr771fs)	Pathogenic
281344	NM_052989.3(IFT122):c.2035del (p.Ser679fs)	Pathogenic
2818768	NM_052989.3(IFT122):c.982C>T (p.Gln328Ter)	Pathogenic
2879426	NM_052989.3(IFT122):c.1963del (p.Glu655fs)	Pathogenic
2913590	NM_052989.3(IFT122):c.1141C>T (p.Gln381Ter)	Pathogenic
3604958	NM_052989.3(IFT122):c.419G>A (p.Trp140Ter)	Pathogenic
3621437	NM_052989.3(IFT122):c.3576G>A (p.Trp1192Ter)	Pathogenic
3647089	NM_052989.3(IFT122):c.3194dup (p.Leu1066fs)	Pathogenic
3679340	NM_052989.3(IFT122):c.2064del (p.Glu689fs)	Pathogenic
3691668	NM_052989.3(IFT122):c.1276_1277insAATGCATG (p.Val426fs)	Pathogenic

SpliceAI

8004 predictions. Top by Δscore:

Variant	Effect	Δscore
3:129433099:TGAGA:T	donor_gain	1.0000
3:129433107:TG:T	donor_gain	1.0000
3:129437946:CTTTG:C	acceptor_gain	1.0000
3:129437948:TTG:T	acceptor_gain	1.0000
3:129437948:TTGCT:T	acceptor_loss	1.0000
3:129437949:TG:T	acceptor_gain	1.0000
3:129437951:C:CC	acceptor_gain	1.0000
3:129437951:CTGGA:C	acceptor_loss	1.0000
3:129439728:A:AC	donor_gain	1.0000
3:129439729:C:CA	donor_gain	1.0000
3:129439729:CCGGA:C	donor_gain	1.0000
3:129449869:A:AG	acceptor_gain	1.0000
3:129449870:G:GG	acceptor_gain	1.0000
3:129458678:G:GG	donor_gain	1.0000
3:129463548:T:A	acceptor_gain	1.0000
3:129463550:T:TA	acceptor_gain	1.0000
3:129469335:T:A	acceptor_gain	1.0000
3:129469340:A:AG	acceptor_gain	1.0000
3:129469341:G:GG	acceptor_gain	1.0000
3:129469341:GA:G	acceptor_gain	1.0000
3:129476659:GCAG:G	acceptor_loss	1.0000
3:129476660:CAGGT:C	acceptor_loss	1.0000
3:129476661:A:AG	acceptor_gain	1.0000
3:129476661:AGGT:A	acceptor_gain	1.0000
3:129476662:G:GG	acceptor_gain	1.0000
3:129476662:GGT:G	acceptor_gain	1.0000
3:129476662:GGTG:G	acceptor_gain	1.0000
3:129476797:GAAAG:G	donor_gain	1.0000
3:129476801:GGTAA:G	donor_loss	1.0000
3:129476802:G:C	donor_loss	1.0000

AlphaMissense

8213 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129458608:T:C	F68S	1.000
3:129458611:C:A	A69D	1.000
3:129458613:T:C	S70P	1.000
3:129458617:G:A	G71E	1.000
3:129458643:T:A	W80R	1.000
3:129458643:T:C	W80R	1.000
3:129458668:T:C	L88P	1.000
3:129461278:T:C	L108P	1.000
3:129463565:T:A	W119R	1.000
3:129463565:T:C	W119R	1.000
3:129464636:T:A	W140R	1.000
3:129464636:T:C	W140R	1.000
3:129478181:T:C	L438P	1.000
3:129479833:T:A	W467R	1.000
3:129479833:T:C	W467R	1.000
3:129481630:C:A	A530D	1.000
3:129483509:T:A	W560R	1.000
3:129483509:T:C	W560R	1.000
3:129488315:C:A	A637D	1.000
3:129449909:T:C	L27P	0.999
3:129458605:G:C	R67P	0.999
3:129458614:C:A	S70Y	0.999
3:129458614:C:T	S70F	0.999
3:129458616:G:A	G71R	0.999
3:129458616:G:C	G71R	0.999
3:129458625:G:C	D74H	0.999
3:129458635:T:A	V77D	0.999
3:129458641:T:A	I79N	0.999
3:129458644:G:C	W80S	0.999
3:129458645:G:C	W80C	0.999

dbSNP variants (sampled 300 via entrez): RS1000045246 (3:129479541 C>G,T), RS1000142536 (3:129450293 GA>G), RS1000230110 (3:129492323 C>T), RS1000297029 (3:129515987 C>G), RS1000344796 (3:129470273 AT>A,ATT), RS1000352468 (3:129487392 C>T), RS1000415413 (3:129456247 G>A,T), RS1000460799 (3:129459006 C>G,T), RS1000504512 (3:129454396 A>T), RS1000504992 (3:129459683 T>A), RS1000513572 (3:129473228 A>G), RS1000532859 (3:129451277 TTTTATTTTTA>T,TTTTATTTTTATTTATTTTTA), RS1000565638 (3:129515805 A>G), RS1000618988 (3:129454529 G>T), RS1000683822 (3:129460223 C>T)

Disease associations

OMIM: gene MIM:606045 | disease phenotypes: MIM:218330

GenCC curated gene-disease

Disease	Classification	Inheritance
cranioectodermal dysplasia 1	Definitive	Autosomal recessive
cranioectodermal dysplasia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cranioectodermal dysplasia 1	Definitive	AR

Mondo (4): cranioectodermal dysplasia 1 (MONDO:0021093), connective tissue disorder (MONDO:0003900), cranioectodermal dysplasia (MONDO:0009032), microcephaly (MONDO:0001149)

Orphanet (1): Cranioectodermal dysplasia (Orphanet:1515)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000506	Telecanthus
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000668	Hypodontia
HP:0000674	Anodontia
HP:0000679	Taurodontia
HP:0000682	Abnormal dental enamel morphology
HP:0000687	Widely spaced teeth
HP:0000691	Microdontia
HP:0000767	Pectus excavatum
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000939	Osteoporosis
HP:0000940	Abnormal diaphysis morphology

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002875_143	Diisocyanate-induced asthma	3.000000e-06
GCST005551_4	Systemic sclerosis (anti-topoisomerase-positive)	3.000000e-06
GCST005956_82	Waist-to-hip ratio adjusted for BMI	2.000000e-07
GCST005958_5	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005962_16	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-11
GCST012227_1258	Hip circumference adjusted for BMI	3.000000e-08
GCST012229_47	Hip index	2.000000e-08
GCST90020024_1257	A body shape index	8.000000e-10
GCST90020026_102	Hip index	8.000000e-24
GCST90020026_224	Hip index	1.000000e-09
GCST90020028_1842	Hip circumference adjusted for BMI	6.000000e-13
GCST90020028_1844	Hip circumference adjusted for BMI	2.000000e-30

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0008537	anti-topoisomerase-I-antibody-positive systemic scleroderma
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases expression, affects cotreatment, increases abundance, increases oxidation	3
Tobacco Smoke Pollution	decreases expression	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Aflatoxin B1	decreases expression, decreases methylation	2
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Vehicle Emissions	decreases reaction, increases expression	1
Coumestrol	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases oxidation, increases abundance, affects cotreatment	1
Smoke	increases abundance, increases expression	1
Theophylline	increases expression, affects cotreatment	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases expression, increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT04184531	Not specified	UNKNOWN	Sensenbrenner Clinical Study
NCT04032756	Not specified	TERMINATED	Tofacitinib Registry of Patients With Ulcerative Colitis in Germany
NCT06626282	Not specified	RECRUITING	Fertility and Ovarian Reserve in Female Childhood Cancer Survivors
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease