TTC21B

Summary

TTC21B (tetratricopeptide repeat domain 21B, HGNC:25660) is a protein-coding gene on chromosome 2q24.3, encoding Tetratricopeptide repeat protein 21B (Q7Z4L5). 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).

This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4.

Source: NCBI Gene 79809 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis 12 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 1,438 total — 71 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 31
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_024753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25660
Approved symbol	TTC21B
Name	tetratricopeptide repeat domain 21B
Location	2q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11457, JBTS11, NPHP12, IFT139B, THM1, FAP60, FLA17, IFT139, CFAP60
Ensembl gene	ENSG00000123607
Ensembl biotype	protein_coding
OMIM	612014
Entrez	79809

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 16 nonsense_mediated_decay, 12 retained_intron, 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000243344, ENST00000392695, ENST00000464374, ENST00000476227, ENST00000484129, ENST00000486672, ENST00000489714, ENST00000497425, ENST00000652557, ENST00000679356, ENST00000679671, ENST00000679676, ENST00000679799, ENST00000679840, ENST00000679931, ENST00000679967, ENST00000680225, ENST00000680249, ENST00000680327, ENST00000680448, ENST00000680657, ENST00000680690, ENST00000680698, ENST00000680888, ENST00000680904, ENST00000680925, ENST00000680947, ENST00000681024, ENST00000681083, ENST00000681167, ENST00000681483, ENST00000681502, ENST00000681606, ENST00000681819, ENST00000681952, ENST00000959804

RefSeq mRNA: 1 — MANE Select: NM_024753 NM_024753

CCDS: CCDS33315

Canonical transcript exons

ENST00000243344 — 29 exons

Exon	Start	End
ENSE00000780096	165883794	165884018
ENSE00000780097	165888279	165888474
ENSE00000840951	165876165	165876232
ENSE00000964346	165912514	165912624
ENSE00001214102	165929135	165929335
ENSE00001214215	165890838	165890988
ENSE00001214269	165915201	165915439
ENSE00001214315	165924549	165924678
ENSE00001341114	165873362	165874832
ENSE00001341157	165898686	165898767
ENSE00001341169	165907678	165907784
ENSE00001341173	165911327	165911465
ENSE00001341179	165913574	165913646
ENSE00001341188	165917257	165917481
ENSE00001341191	165919276	165919433
ENSE00003485366	165945524	165945690
ENSE00003532409	165929650	165929747
ENSE00003535807	165932973	165933057
ENSE00003552611	165890479	165890640
ENSE00003553425	165931758	165931856
ENSE00003586930	165949394	165949504
ENSE00003587594	165941027	165941184
ENSE00003594318	165901722	165901910
ENSE00003620395	165899770	165899880
ENSE00003630213	165943219	165943341
ENSE00003664554	165930172	165930364
ENSE00003668440	165949595	165949724
ENSE00003677568	165880679	165880799
ENSE00003846812	165953685	165953776

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 95.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6398 / max 160.4231, expressed in 1719 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31674	10.4082	1717
31672	0.1327	60
31673	0.0990	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.77	gold quality
calcaneal tendon	UBERON:0003701	91.86	gold quality
cerebellar hemisphere	UBERON:0002245	90.19	gold quality
cerebellar cortex	UBERON:0002129	89.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.83	gold quality
sural nerve	UBERON:0015488	88.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.41	gold quality
ventricular zone	UBERON:0003053	88.20	gold quality
tibial nerve	UBERON:0001323	87.38	gold quality
cerebellum	UBERON:0002037	86.32	gold quality
adrenal tissue	UBERON:0018303	85.91	gold quality
endocervix	UBERON:0000458	85.08	gold quality
left ovary	UBERON:0002119	84.80	gold quality
right ovary	UBERON:0002118	84.75	gold quality
right frontal lobe	UBERON:0002810	84.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.37	gold quality
cortical plate	UBERON:0005343	84.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.32	gold quality
gastrocnemius	UBERON:0001388	84.20	gold quality
ectocervix	UBERON:0012249	84.16	gold quality
muscle of leg	UBERON:0001383	84.13	gold quality
body of pancreas	UBERON:0001150	84.10	gold quality
ganglionic eminence	UBERON:0004023	83.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.87	gold quality
metanephros cortex	UBERON:0010533	83.74	gold quality
mucosa of stomach	UBERON:0001199	83.63	gold quality
body of uterus	UBERON:0009853	83.60	gold quality
right lung	UBERON:0002167	83.16	gold quality
skin of leg	UBERON:0001511	82.63	gold quality
adenohypophysis	UBERON:0002196	82.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting TTC21B, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• TTC21B contributes pathogenic alleles to approximately 5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes (PMID:21258341)
• We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. (PMID:24876116)
• Exome sequencing and further CRB2 analysis revealed that both siblings are compound heterozygotes for CRB2 mutations p.N800K and p.Gly1036Alafs*43, and heterozygous for a deleterious splice variant in the ciliopathy gene TTCB21 (PMID:26925547)
• TTC21B mutation is associated with glomerular and cystic kidney diseases. (PMID:26940125)
• Case Reports: 3 novel TTC21B mutations in two Chinese pediatric nephronophthisis-related ciliopathies cases that both presented with end-stage renal disease. (PMID:28124483)
• A novel heterotaxy gene: Expansion of the phenotype of TTC21B-spectrum disease. (PMID:33547761)
• Retinal dystrophy as part of TTC21B-associated ciliopathy. (PMID:33599192)
• Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B. (PMID:35695966)
• Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes. (PMID:36273201)
• Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants. (PMID:38439578)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttc21b	ENSDARG00000012368
mus_musculus	Ttc21b	ENSMUSG00000034848
rattus_norvegicus	Ttc21b	ENSRNOG00000005868
caenorhabditis_elegans		WBGENE00022696

Paralogs (1): TTC21A (ENSG00000168026)

Protein

Protein identifiers

Tetratricopeptide repeat protein 21B — Q7Z4L5 (reviewed: Q7Z4L5)

Alternative names: Intraflagellar transport 139 homolog

All UniProt accessions (17): A0A494C0N4, A0A7P0T8P4, A0A7P0T962, A0A7P0T968, Q7Z4L5, A0A7P0T9H7, A0A7P0TA66, A0A7P0TAA5, A0A7P0TAJ8, A0A7P0TAK1, A0A7P0TB56, A0A7P0TB61, A0A7P0TBE5, A0A7P0TBF6, A0A7P0Z487, A0A7P0Z4B3, H9KV93

UniProt curated annotations — full annotation on UniProt →

Function. 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). Essential for retrograde trafficking of IFT-1, IFT-B and GPCRs. Negatively modulates the SHH signal transduction.

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 directy with WDR35 and TTC21B. Interacts with TTC25.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium axoneme.

Disease relevance. Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. TTC21B is causally associated with diverse ciliopathies. It also acts as a modifier gene across the ciliopathy spectrum, interacting in trans with mutations in other ciliopathy-causing genes and contributing to disease manifestation and severity. Nephronophthisis 12 (NPHP12) [MIM:613820] An autosomal recessive disorder resulting in end-stage renal disease. It is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Some patients manifest extra-renal features including retinal, skeletal and central nervous system defects. The disease is caused by variants affecting the gene represented in this entry. Short-rib thoracic dysplasia 4 with or without polydactyly (SRTD4) [MIM:613819] 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. Joubert syndrome 11 (JBTS11) [MIM:613820] 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 and renal disease. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TTC21 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z4L5-1	1	yes
Q7Z4L5-2	2

RefSeq proteins (1): NP_079029* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR040364	TTC21A/TTC21B	Family
IPR056832	ARM_TT21_2nd	Domain
IPR056833	ARM_TT21_N	Domain
IPR056834	ARM_TT21_C	Domain
IPR056835	ARM_TT21_5th	Domain
IPR056836	ARM_TT21_4th	Domain

Pfam: PF13181, PF25058, PF25060, PF25062, PF25063, PF25064, PF25068

UniProt features (154 total): helix 77, sequence variant 46, repeat 19, turn 5, sequence conflict 3, splice variant 2, chain 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z4L5-F1	83.39	0.08

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: 232 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_CEREBELLAR_PURKINJE_CELL_LAYER_FORMATION, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_VENTRICULAR_SYSTEM_DEVELOPMENT, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_REGIONALIZATION, GOBP_REGULATION_OF_BEHAVIOR

GO Biological Process (18): regulation of transcription by RNA polymerase II (GO:0006357), smoothened signaling pathway (GO:0007224), regulation of smoothened signaling pathway (GO:0008589), positive regulation of gene expression (GO:0010628), ventricular system development (GO:0021591), cerebellar Purkinje cell differentiation (GO:0021702), forebrain dorsal/ventral pattern formation (GO:0021798), intraciliary retrograde transport (GO:0035721), Bergmann glial cell differentiation (GO:0060020), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), positive regulation of canonical Wnt signaling pathway (GO:0090263), protein localization to non-motile cilium (GO:0097499), negative regulation of eating behavior (GO:1903999), regulation of intraciliary retrograde transport (GO:1905799), regulation of gene expression (GO:0010468), cerebellum development (GO:0021549), forebrain development (GO:0030900)

GO Molecular Function (2): chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (7): cilium (GO:0005929), axoneme (GO:0005930), intraciliary transport particle A (GO:0030991), ciliary tip (GO:0097542), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), 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	4
gene expression	2
brain development	2
protein localization to cilium	2
anatomical structure development	2
binding	2
intraciliary transport particle	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cell surface receptor signaling pathway	1
smoothened signaling pathway	1
regulation of signal transduction	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
system development	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
central nervous system neuron differentiation	1
dorsal/ventral pattern formation	1
forebrain regionalization	1
intraciliary transport	1
astrocyte differentiation	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
protein localization to organelle	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
eating behavior	1
regulation of eating behavior	1
negative regulation of feeding behavior	1
regulation of intracellular transport	1
intraciliary retrograde transport	1
regulation of microtubule-based movement	1
regulation of macromolecule biosynthetic process	1

Protein interactions and networks

STRING

1484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTC21B	WDR35	Q9P2L0	997
TTC21B	IFT43	Q96FT9	996
TTC21B	IFT140	Q96RY7	995
TTC21B	IFT122	Q9HBG6	995
TTC21B	WDR19	Q8NEZ3	994
TTC21B	IFT88	Q13099	935
TTC21B	TULP3	O75386	907
TTC21B	IFT81	Q8WYA0	869
TTC21B	IFT74	Q96LB3	858
TTC21B	KIF3A	Q9Y496	829
TTC21B	RAB23	Q9ULC3	803
TTC21B	IFT52	Q9Y366	803
TTC21B	IFT172	Q9UG01	801
TTC21B	DYNC2H1	Q8NCM8	791
TTC21B	IFT57	Q9NWB7	791

IntAct

50 interactions, top by confidence:

A	B	Type	Score
WDR19	TULP3	psi-mi:“MI:0914”(association)	0.860
TULP3	TTC21B	psi-mi:“MI:0914”(association)	0.840
TTC21B	TULP3	psi-mi:“MI:0914”(association)	0.840
TULP3	FOXK2	psi-mi:“MI:0914”(association)	0.790
IFT43	TULP3	psi-mi:“MI:0914”(association)	0.790
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
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
IFT43	TTC21B	psi-mi:“MI:0914”(association)	0.530
SPACA1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
DOC2A	DOC2B	psi-mi:“MI:0914”(association)	0.530
TULP3	HSPG2	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
SV2A	EXTL3	psi-mi:“MI:0914”(association)	0.530
IFT122	CDC7	psi-mi:“MI:0914”(association)	0.510
IFT140	ACSL3	psi-mi:“MI:0914”(association)	0.510
TTC21B	VCL	psi-mi:“MI:0914”(association)	0.510
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
IFT122	TTC21B	psi-mi:“MI:0915”(physical association)	0.400
IFT43	PLK1	psi-mi:“MI:0914”(association)	0.350
	TTC21B	psi-mi:“MI:0914”(association)	0.350
WDR35	TTC21B	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
TULP3	PPP1R12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Synthetic Lethality), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), TTC21B (Affinity Capture-MS)

ESM2 similar proteins: A1L1K3, A2AKQ8, A2VE45, A4IHR1, A6H739, A7YE96, A8WE67, A8XBR9, B0WYS3, B2RYD6, B3M1B7, B3P0R4, B4GF49, B4HE12, B4JHK2, B4K4X6, B4M4L4, B4NKT1, B4PS83, B4QZ45, E9Q6P5, Q0HA38, Q13099, Q16JL4, Q16NZ8, Q296H8, Q29L58, Q4QQS2, Q4QR29, Q5RE52, Q5RFR8, Q61371, Q62018, Q6DEU9, Q6INU8, Q6PD62, Q7PRA4, Q7Z4L5, Q86TV6, Q86WT1

Diamond homologs: Q0HA38, Q6INC1, Q7Z4L5, Q8C0S4, Q8NDW8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TTC21B	“form complex”	“ITF complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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	5	37.1×	3e-05
Hedgehog ‘off’ state	5	33.0×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
intraciliary retrograde transport	5	165.2×	2e-08
protein localization to cilium	5	59.0×	3e-06
cilium assembly	5	10.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1438 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	47
Uncertain significance	615
Likely benign	483
Benign	77

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179040	NM_024753.5(TTC21B):c.3087del (p.Gly1030fs)	Pathogenic
1179137	NM_024753.5(TTC21B):c.264_267dupTAGA	Pathogenic
1344652	NM_024753.5(TTC21B):c.1038G>A (p.Trp346Ter)	Pathogenic
1350763	NM_024753.5(TTC21B):c.2818C>T (p.Gln940Ter)	Pathogenic
1351437	NM_024753.5(TTC21B):c.3164G>A (p.Trp1055Ter)	Pathogenic
1361272	NM_024753.5(TTC21B):c.2337T>G (p.Tyr779Ter)	Pathogenic
1363403	NM_024753.5(TTC21B):c.3044del (p.Arg1015fs)	Pathogenic
1372589	NM_024753.5(TTC21B):c.3144del (p.Ala1049fs)	Pathogenic
1379421	NM_024753.5(TTC21B):c.1263_1266dup (p.Leu423fs)	Pathogenic
1392901	NM_024753.5(TTC21B):c.1138C>T (p.Gln380Ter)	Pathogenic
1417573	NM_024753.5(TTC21B):c.3112G>T (p.Glu1038Ter)	Pathogenic
1424345	NM_024753.5(TTC21B):c.1007_1025del (p.Leu336fs)	Pathogenic
1436713	NM_024753.5(TTC21B):c.1575T>G (p.Tyr525Ter)	Pathogenic
1451840	NM_024753.5(TTC21B):c.3045del (p.Asn1016fs)	Pathogenic
1456585	NM_024753.5(TTC21B):c.1346T>G (p.Leu449Ter)	Pathogenic
1457474	NM_024753.5(TTC21B):c.2692C>T (p.Arg898Ter)	Pathogenic
1458640	NM_024753.5(TTC21B):c.3076C>T (p.Gln1026Ter)	Pathogenic
1458764	NM_024753.5(TTC21B):c.1942dup (p.Ser648fs)	Pathogenic
1904055	NM_024753.5(TTC21B):c.1947_1948del (p.Thr650fs)	Pathogenic
1904546	NM_024753.5(TTC21B):c.1126_1127insGT (p.Asp376fs)	Pathogenic
1971343	NM_024753.5(TTC21B):c.2455G>T (p.Glu819Ter)	Pathogenic
1999508	NM_024753.5(TTC21B):c.1087G>T (p.Gly363Ter)	Pathogenic
2001013	NM_024753.5(TTC21B):c.3731_3732del (p.Glu1244fs)	Pathogenic
2014938	NM_024753.5(TTC21B):c.1162C>T (p.Gln388Ter)	Pathogenic
2026752	NM_024753.5(TTC21B):c.996C>A (p.Tyr332Ter)	Pathogenic
2026911	NM_024753.5(TTC21B):c.244_248del (p.Lys82fs)	Pathogenic
2035876	NM_024753.5(TTC21B):c.1840del (p.Ser614fs)	Pathogenic
2053254	NM_024753.5(TTC21B):c.2297_2298del (p.Leu766fs)	Pathogenic
2068220	NM_024753.5(TTC21B):c.3380dup (p.Asn1127fs)	Pathogenic
2105663	NM_024753.5(TTC21B):c.3592_3596del (p.Lys1198fs)	Pathogenic

SpliceAI

4156 predictions. Top by Δscore:

Variant	Effect	Δscore
2:165880673:ACTC:A	donor_loss	1.0000
2:165880674:CTCA:C	donor_loss	1.0000
2:165880675:TCA:T	donor_loss	1.0000
2:165880678:C:A	donor_loss	1.0000
2:165880678:CCTA:C	donor_gain	1.0000
2:165880681:A:AC	donor_gain	1.0000
2:165880682:C:CC	donor_gain	1.0000
2:165880795:CAAGA:C	acceptor_gain	1.0000
2:165880796:AAGA:A	acceptor_gain	1.0000
2:165880797:AGA:A	acceptor_gain	1.0000
2:165880797:AGAC:A	acceptor_loss	1.0000
2:165880798:GA:G	acceptor_gain	1.0000
2:165880799:ACTGA:A	acceptor_loss	1.0000
2:165880800:C:CC	acceptor_gain	1.0000
2:165880801:T:C	acceptor_loss	1.0000
2:165883789:CCTA:C	donor_gain	1.0000
2:165883790:CTACT:C	donor_loss	1.0000
2:165883791:TA:T	donor_loss	1.0000
2:165883792:A:AC	donor_gain	1.0000
2:165883793:C:CC	donor_gain	1.0000
2:165883793:C:G	donor_loss	1.0000
2:165883793:CT:C	donor_gain	1.0000
2:165883793:CTCT:C	donor_gain	1.0000
2:165884014:TCCTT:T	acceptor_gain	1.0000
2:165884015:CCTTC:C	acceptor_gain	1.0000
2:165884016:CTT:C	acceptor_gain	1.0000
2:165884017:TT:T	acceptor_gain	1.0000
2:165884019:C:CC	acceptor_gain	1.0000
2:165884021:A:AC	acceptor_gain	1.0000
2:165884021:A:C	acceptor_gain	1.0000

AlphaMissense

8667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:165876220:G:T	A1273E	0.998
2:165880771:C:T	G1238E	0.998
2:165880772:C:G	G1238R	0.998
2:165880772:C:T	G1238R	0.998
2:165883868:C:G	A1204P	0.998
2:165883935:C:A	K1181N	0.998
2:165883935:C:G	K1181N	0.998
2:165883937:T:C	K1181E	0.998
2:165883939:A:G	L1180P	0.998
2:165883947:T:A	R1177S	0.998
2:165883947:T:G	R1177S	0.998
2:165883951:G:T	A1176D	0.998
2:165883988:C:G	A1164P	0.998
2:165876223:A:G	L1272P	0.997
2:165880735:G:T	A1250D	0.997
2:165883948:C:G	R1177T	0.997
2:165883867:G:T	A1204D	0.996
2:165883870:A:G	L1203P	0.996
2:165883873:A:G	L1202P	0.996
2:165883952:C:G	A1176P	0.996
2:165883982:C:G	A1166P	0.996
2:165880736:C:G	A1250P	0.995
2:165890851:C:G	G1030R	0.995
2:165890851:C:T	G1030R	0.995
2:165876204:T:A	K1278N	0.994
2:165876204:T:G	K1278N	0.994
2:165883876:A:G	L1201P	0.994
2:165883987:G:T	A1164E	0.994
2:165890850:C:T	G1030E	0.994
2:165917448:C:G	A570P	0.994

dbSNP variants (sampled 300 via entrez): RS1000011119 (2:165949200 C>T), RS1000036276 (2:165905553 A>G), RS1000049925 (2:165947631 G>A,T), RS1000061237 (2:165911633 T>C), RS1000061560 (2:165944899 G>A), RS1000097545 (2:165944459 T>C), RS1000113518 (2:165902361 A>C), RS1000238065 (2:165882598 C>G,T), RS1000289247 (2:165908808 C>A), RS1000365953 (2:165892749 T>G), RS1000425339 (2:165932043 A>C), RS1000580160 (2:165886531 G>T), RS1000623424 (2:165897502 G>A), RS1000626834 (2:165884501 T>C), RS1000671395 (2:165922088 TTAAG>T)

Disease associations

OMIM: gene MIM:612014 | disease phenotypes: MIM:613819, MIM:613820, MIM:208500, MIM:256100, MIM:615981, MIM:213300, MIM:256300, MIM:602088, MIM:266900, MIM:263520, MIM:269860, MIM:607745, MIM:613721, MIM:613863, MIM:201300

GenCC curated gene-disease

Disease	Classification	Inheritance
asphyxiating thoracic dystrophy 4	Definitive	Autosomal recessive
nephronophthisis 12	Strong	Autosomal recessive
Jeune syndrome	Supportive	Autosomal recessive
nephronophthisis 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nephronophthisis 12	Definitive	AR

Mondo (22): asphyxiating thoracic dystrophy 4 (MONDO:0013441), nephronophthisis 12 (MONDO:0013442), Jeune syndrome (MONDO:0018770), nephronophthisis (MONDO:0019005), connective tissue disorder (MONDO:0003900), Bardet-Biedl syndrome 2 (MONDO:0014432), chronic kidney disease (MONDO:0005300), Joubert syndrome 1 (MONDO:0008944), nephrotic syndrome (MONDO:0005377), congenital nephrotic syndrome, Finnish type (MONDO:0009732), nephronophthisis 2 (MONDO:0011190), Senior-Loken syndrome (MONDO:0017842), inherited retinal dystrophy (MONDO:0019118), short-rib thoracic dysplasia 6 with or without polydactyly (MONDO:0009894), Beemer-Langer syndrome (MONDO:0010024)

Orphanet (14): Jeune syndrome (Orphanet:474), Nephronophthisis (Orphanet:655), Bardet-Biedl syndrome (Orphanet:110), Senior-Loken syndrome (Orphanet:3156), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Congenital nephrotic syndrome, Finnish type (Orphanet:839), Infantile nephronophthisis (Orphanet:93591), Short rib-polydactyly syndrome, Beemer-Langer type (Orphanet:93268), Dravet syndrome (Orphanet:33069), Self-limited neonatal-infantile epilepsy (Orphanet:140927), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Self-limited infantile epilepsy (Orphanet:306), Genetic epilepsy with febrile seizure plus (Orphanet:36387), Hereditary sensory and autonomic neuropathy type 2 (Orphanet:970)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000090	Nephronophthisis
HP:0000112	Nephropathy
HP:0000766	Abnormal sternum morphology
HP:0000772	Abnormal rib morphology
HP:0000774	Narrow chest
HP:0000889	Abnormal clavicle morphology
HP:0000944	Abnormal metaphysis morphology
HP:0001156	Brachydactyly
HP:0001162	Postaxial hand polydactyly
HP:0001392	Abnormality of the liver
HP:0001407	Hepatic cysts
HP:0001770	Toe syndactyly
HP:0001773	Short foot
HP:0001830	Postaxial foot polydactyly
HP:0002093	Respiratory insufficiency
HP:0002644	Abnormal pelvic girdle bone morphology
HP:0002650	Scoliosis
HP:0002652	Skeletal dysplasia
HP:0002983	Micromelia
HP:0003026	Short long bone
HP:0003774	Stage 5 chronic kidney disease
HP:0004322	Short stature
HP:0006703	Aplasia/Hypoplasia of the lungs
HP:0007703	Abnormal retinal pigmentation
HP:0008872	Feeding difficulties in infancy
HP:0010306	Short thorax
HP:0010442	Polydactyly

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003098_5	Diabetic kidney disease	5.000000e-06
GCST006143_8	Bone mineral density (total hip)	4.000000e-06
GCST007343_2	Epilepsy	2.000000e-13
GCST007352_1	Focal epilepsy	7.000000e-09
GCST007353_3	Generalized epilepsy	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007702	hip bone mineral density

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D004827	Epilepsy	C10.228.140.490
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D058499	Retinal Dystrophies	C11.768.585.658
C537910	Bardet-Biedl syndrome 2 (supp.)
C567827	Generalized Epilepsy With Febrile Seizures Plus, 7 (supp.)
C537571	Jeune syndrome (supp.)
C566582	Nephronophthisis 2 (supp.)
C537580	Senior Loken Syndrome (supp.)
C537599	Short rib-polydactyly syndrome, Beemer type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
sodium arsenite	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Manganese	increases abundance, increases expression	1
Nickel	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

209 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
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD