TULP3

Summary

TULP3 (TUB like protein 3, HGNC:12425) is a protein-coding gene on chromosome 12p13.33, encoding Tubby-related protein 3 (O75386). Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein-coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh si….

This gene encodes a member of the tubby gene family of bipartite transcription factors. Members of this family have been identified in plants, vertebrates, and invertebrates, and they share a conserved N-terminal transcription activation region and a conserved C-terminal DNA and phosphatidylinositol-phosphate binding region. The encoded protein binds to phosphoinositides in the plasma membrane via its C-terminal region and probably functions as a membrane-bound transcription regulator that translocates to the nucleus in response to phosphoinositide hydrolysis, for instance, induced by G-protein-coupled-receptor signaling. It plays an important role in neuronal development and function. Two transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 7289 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 124 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• MANE Select transcript: NM_003324

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12425
Approved symbol	TULP3
Name	TUB like protein 3
Location	12p13.33
Locus type	gene with protein product
Status	Approved
Aliases	TUBL3
Ensembl gene	ENSG00000078246
Ensembl biotype	protein_coding
OMIM	604730
Entrez	7289

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 nonsense_mediated_decay

ENST00000397132, ENST00000448120, ENST00000538354, ENST00000538704, ENST00000540184, ENST00000541678, ENST00000544943, ENST00000545331, ENST00000864013, ENST00000864014, ENST00000935913, ENST00000935914

RefSeq mRNA: 2 — MANE Select: NM_003324 NM_001160408, NM_003324

CCDS: CCDS53737, CCDS8519

Canonical transcript exons

ENST00000448120 — 11 exons

Exon	Start	End
ENSE00001350775	2920763	2920922
ENSE00001596418	2939311	2941138
ENSE00003232583	2890891	2890988
ENSE00003461147	2930248	2930345
ENSE00003551544	2922262	2922402
ENSE00003555533	2938114	2938285
ENSE00003558577	2934447	2934561
ENSE00003563956	2931037	2931240
ENSE00003575506	2937631	2937729
ENSE00003684072	2909529	2909580
ENSE00003692597	2933418	2933530

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.5906 / max 380.9317, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123454	49.5906	1817
123455	10.7329	1734
123456	2.7272	1360

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.57	gold quality
oocyte	CL:0000023	98.74	gold quality
nipple	UBERON:0002030	95.20	gold quality
cardia of stomach	UBERON:0001162	93.34	gold quality
ventricular zone	UBERON:0003053	93.12	gold quality
cartilage tissue	UBERON:0002418	92.61	gold quality
bronchial epithelial cell	CL:0002328	92.58	gold quality
endocervix	UBERON:0000458	92.43	gold quality
renal medulla	UBERON:0000362	92.40	gold quality
pylorus	UBERON:0001166	92.39	gold quality
left ovary	UBERON:0002119	92.39	gold quality
calcaneal tendon	UBERON:0003701	92.27	gold quality
tendon of biceps brachii	UBERON:0008188	91.97	gold quality
stromal cell of endometrium	CL:0002255	91.84	gold quality
cervix squamous epithelium	UBERON:0006922	91.71	gold quality
epithelium of bronchus	UBERON:0002031	91.64	gold quality
ganglionic eminence	UBERON:0004023	91.60	gold quality
bronchus	UBERON:0002185	91.45	gold quality
urethra	UBERON:0000057	91.36	gold quality
ectocervix	UBERON:0012249	91.34	gold quality
right ovary	UBERON:0002118	91.24	gold quality
ovary	UBERON:0000992	91.19	gold quality
uterine cervix	UBERON:0000002	90.96	gold quality
synovial joint	UBERON:0002217	90.55	gold quality
hair follicle	UBERON:0002073	90.52	gold quality
tendon	UBERON:0000043	90.48	gold quality
body of uterus	UBERON:0009853	90.44	gold quality
pericardium	UBERON:0002407	90.35	gold quality
popliteal artery	UBERON:0002250	90.33	gold quality
cerebellar vermis	UBERON:0004720	90.33	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.58
E-GEOD-124858	no	152.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX2

miRNA regulators (miRDB)

85 targeting TULP3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AC	99.84	70.77	4351

Literature-anchored findings (GeneRIF, showing 6)

• Data demonstrated that pancreatic cancer patients exhibiting high transcriptional levels of TULP3 showed a poor overall survival rate. (PMID:24668219)
• Formation of primary cilia is downregulated in TULP3-knockout (KO) RPE1 cells. ARL13B and INPP5E fail to localize to primary cilia in TULP3-KO cells. (PMID:30583862)
• TULP3 expression levels were increased in colorectal cancer when compared to the adjacent non-tumoral tissue. In addition, higher TULP3 gene expression was associated to lymphatic and vascular invasion in colon adenocarcinoma and rectum adenocarcinoma, respectively. (PMID:30640939)
• MicroRNA-506 has a suppressive effect on the tumorigenesis of nonsmall-cell lung cancer by regulating tubby-like protein 3. (PMID:34874810)
• TULP3 silencing suppresses cell proliferation, migration and invasion in gastric cancer via the PTEN/Akt/Snail pathway. (PMID:35344762)
• Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. (PMID:35397207)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tulp3	ENSDARG00000063672
mus_musculus	Tulp3	ENSMUSG00000001521
rattus_norvegicus	Tulp3	ENSRNOG00000005767
drosophila_melanogaster	ktub	FBGN0015721

Paralogs (5): TULP2 (ENSG00000104804), TULP1 (ENSG00000112041), WDR35 (ENSG00000118965), TULP4 (ENSG00000130338), TUB (ENSG00000166402)

Protein

Protein identifiers

Tubby-related protein 3 — O75386 (reviewed: O75386)

Alternative names: Tubby-like protein 3

All UniProt accessions (5): O75386, F5GWL5, F5H7B9, H0YFU8, H0YG12

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein-coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh signaling. Binds to phosphorylated inositide (phosphoinositide) lipids. Both IFT-A- and phosphoinositide-binding properties are required to regulate ciliary G protein-coupled receptor trafficking. During adipogenesis, regulates ciliary trafficking of FFAR4 in preadipocytes.

Subunit / interactions. Associates with the IFT complex A (IFT-A). Interacts with SIRT1.

Subcellular location. Nucleus. Cell membrane. Cell projection. Cilium. Cytoplasm. Secreted.

Tissue specificity. Expressed at high levels in testis, ovaries, thyroid, and spinal cord.

Disease relevance. Hepatorenocardiac degenerative fibrosis (HRCDF) [MIM:619902] An autosomal recessive disorder characterized by progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. Disease onset is variable, ranging from childhood to adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TUB family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75386-1	1	yes
O75386-2	2
O75386-3	3

RefSeq proteins (2): NP_001153880, NP_003315* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000007	Tubby_C	Domain
IPR005398	Tubby_N	Domain
IPR018066	Tubby_C_CS	Conserved_site
IPR025659	Tubby-like_C	Homologous_superfamily

Pfam: PF01167, PF16322

UniProt features (20 total): sequence conflict 6, splice variant 4, sequence variant 3, region of interest 2, mutagenesis site 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8FH3	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75386-F1	73.51	0.43

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
24–34	in mut12; abolishes association with the ift complex a (ift-a) without affecting phosphoinositide binding. impaired loca
268–270	in tulp3kr; abolishes phosphoinositide binding and impairs localization to cilia. still associates with the ift complex

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state

MSigDB gene sets: 264 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MYAATNNNNNNNGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, BROWNE_HCMV_INFECTION_48HR_DN

GO Biological Process (23): neural tube closure (GO:0001843), regulation of DNA-templated transcription (GO:0006355), G protein-coupled receptor signaling pathway (GO:0007186), brain development (GO:0007420), regulation of G protein-coupled receptor signaling pathway (GO:0008277), anterior/posterior pattern specification (GO:0009952), spinal cord dorsal/ventral patterning (GO:0021513), central nervous system neuron differentiation (GO:0021953), embryonic camera-type eye development (GO:0031076), embryonic digit morphogenesis (GO:0042733), negative regulation of smoothened signaling pathway (GO:0045879), embryonic neurocranium morphogenesis (GO:0048702), bone development (GO:0060348), bronchus morphogenesis (GO:0060434), smoothened signaling pathway involved in dorsal/ventral neural tube patterning (GO:0060831), protein localization to cilium (GO:0061512), ganglion development (GO:0061548), neural tube formation (GO:0001841), smoothened signaling pathway (GO:0007224), regulation of smoothened signaling pathway (GO:0008589), dorsal/ventral neural tube patterning (GO:0021904), neural tube development (GO:0021915), limb development (GO:0060173)

GO Molecular Function (7): G protein-coupled receptor binding (GO:0001664), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), enzyme binding (GO:0019899), phosphatidylinositol binding (GO:0035091), protein-containing complex binding (GO:0044877), intraciliary transport particle A binding (GO:0120160), protein binding (GO:0005515)

GO Cellular Component (14): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), ciliary base (GO:0097546), 9+0 non-motile cilium (GO:0097731), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Hedgehog	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
smoothened signaling pathway	3
cilium	3
central nervous system development	2
animal organ development	2
regulation of signal transduction	2
embryonic morphogenesis	2
binding	2
nuclear lumen	2
primary neural tube formation	1
tube closure	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
G protein-coupled receptor activity	1
signal transduction	1
head development	1
G protein-coupled receptor signaling pathway	1
regionalization	1
dorsal/ventral pattern formation	1
spinal cord patterning	1
neuron differentiation	1
camera-type eye development	1
embryonic organ development	1
embryonic limb morphogenesis	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
embryonic cranial skeleton morphogenesis	1
skeletal system development	1
animal organ morphogenesis	1
tube morphogenesis	1
bronchus development	1
dorsal/ventral neural tube patterning	1
protein localization to organelle	1
nervous system development	1
tissue development	1
embryonic epithelial tube formation	1
neural tube development	1
cell surface receptor signaling pathway	1
signaling receptor binding	1

Protein interactions and networks

STRING

1342 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TULP3	TTC21B	Q7Z4L5	907
TULP3	GPR161	Q8N6U8	843
TULP3	RAB23	Q9ULC3	790
TULP3	IFT122	Q9HBG6	784
TULP3	IFT140	Q96RY7	757
TULP3	MCHR1	Q99705	722
TULP3	ARL13B	Q3SXY8	721
TULP3	IFT88	Q13099	715
TULP3	GLI3	P10071	705
TULP3	GNAQ	P50148	690
TULP3	SMO	Q99835	679
TULP3	SUFU	Q9UMX1	664
TULP3	IFT27	Q9BW83	647
TULP3	GLI2	P10070	628
TULP3	KIF3A	Q9Y496	616

IntAct

141 interactions, top by confidence:

A	B	Type	Score
ANKRD54	TULP3	psi-mi:“MI:0915”(physical association)	0.930
TULP3	ANKRD54	psi-mi:“MI:0915”(physical association)	0.930
ANKRD54	TULP3	psi-mi:“MI:0914”(association)	0.930
ACBD6	NMT2	psi-mi:“MI:0914”(association)	0.870
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
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
TULP3	MAGEA6	psi-mi:“MI:0915”(physical association)	0.780
MAGEA6	TULP3	psi-mi:“MI:0915”(physical association)	0.780
TULP3	SIRT1	psi-mi:“MI:0915”(physical association)	0.770
TULP3	BACH2	psi-mi:“MI:0915”(physical association)	0.740
PSTPIP1	TULP3	psi-mi:“MI:0915”(physical association)	0.720
TULP3	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640

BioGRID (443): TULP3 (Two-hybrid), PSTPIP1 (Two-hybrid), ROPN1 (Two-hybrid), ANKRD54 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-1 (Two-hybrid), KRTAP10-5 (Two-hybrid), TULP3 (Proximity Label-MS), TTC21B (Affinity Capture-MS), WDR35 (Affinity Capture-MS), ANKRD54 (Affinity Capture-MS), LYSMD1 (Affinity Capture-MS), WDR19 (Affinity Capture-MS), TULP3 (Affinity Capture-MS), IFT140 (Affinity Capture-MS)

ESM2 similar proteins: A0PG75, A2A3N6, A7T1N0, A8XKF2, B3H5L1, D4A2Z8, E9PU17, E9PX95, F1S5L4, F4IM84, O08619, O15162, O42857, O75386, P00488, P34751, P41879, P47140, P58195, P58196, P97564, Q05187, Q05B79, Q09306, Q0KHU5, Q28C60, Q3UW68, Q3ZBG9, Q5GJ77, Q5XI69, Q69RI8, Q6DCK1, Q6DNF3, Q6QBQ4, Q6S5G3, Q84M24, Q8IJH8, Q8VHK9, Q9DCW2, Q9FHK8

Diamond homologs: A8WN62, B0WI30, B0XFQ9, B3MDU3, B3NJY0, B4H4X0, B4I7J9, B4J6R7, B4KNA9, B4LMR9, B4MKC7, B4P9H8, B4QFM2, O00294, O00295, O75386, O88413, O88808, P46686, P50586, P50607, Q09306, Q0WPY0, Q10LG8, Q16IR1, Q16KI5, Q28X18, Q2QXB2, Q53PP5, Q5QM27, Q688Y7, Q68Y48, Q69U54, Q6NPQ1, Q6Z2G9, Q75HX5, Q7PZK5, Q7XSV4, Q86PC9, Q8GVE5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TULP3	“up-regulates activity”	GPR161	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
Striated Muscle Contraction	6	27.6×	1e-05
Intraflagellar transport	7	20.9×	1e-05
Hedgehog ‘off’ state	7	18.6×	1e-05
Muscle contraction	9	10.4×	1e-05
RAF/MAP kinase cascade	6	5.5×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
intraciliary retrograde transport	6	76.6×	6e-08
sarcomere organization	7	30.5×	9e-07
protein localization to cilium	5	22.8×	6e-04
Ras protein signal transduction	6	14.0×	7e-04
muscle organ development	6	11.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	74
Likely benign	13
Benign	3

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1687113	NM_003324.5:c.(41+1_42-1)_(696+1_697-1)del	Pathogenic
1687115	NM_003324.5(TULP3):c.1023+1G>A	Pathogenic
1687116	NM_003324.5(TULP3):c.70C>T (p.Arg24Ter)	Pathogenic
1687117	NM_003324.5(TULP3):c.544del (p.Leu182fs)	Pathogenic
1687118	NM_003324.5(TULP3):c.1223G>A (p.Arg408His)	Pathogenic
1693114	NM_003324.5(TULP3):c.1144C>T (p.Arg382Trp)	Pathogenic
2444270	NM_003324.5(TULP3):c.809+2T>C	Pathogenic
3897998	NM_003324.5(TULP3):c.492+1G>A	Likely pathogenic
4277815	NM_003324.5(TULP3):c.1258del (p.Tyr420fs)	Likely pathogenic
4849437	NM_003324.5(TULP3):c.810-1G>C	Likely pathogenic

SpliceAI

2505 predictions. Top by Δscore:

Variant	Effect	Δscore
12:2877278:GGCTG:G	donor_gain	1.0000
12:2877279:GCTGG:G	donor_gain	1.0000
12:2877282:GGT:G	donor_loss	1.0000
12:2877283:GTAAG:G	donor_loss	1.0000
12:2877284:T:A	donor_loss	1.0000
12:2909527:A:AG	acceptor_gain	1.0000
12:2909528:G:GT	acceptor_gain	1.0000
12:2909528:GT:G	acceptor_gain	1.0000
12:2909576:ATCAG:A	donor_loss	1.0000
12:2909578:CAG:C	donor_loss	1.0000
12:2909579:AG:A	donor_loss	1.0000
12:2909580:GG:G	donor_loss	1.0000
12:2909581:GTGA:G	donor_loss	1.0000
12:2909582:T:G	donor_loss	1.0000
12:2922260:A:AG	acceptor_gain	1.0000
12:2922260:AG:A	acceptor_gain	1.0000
12:2922261:G:GT	acceptor_gain	1.0000
12:2922261:GG:G	acceptor_gain	1.0000
12:2922261:GGT:G	acceptor_gain	1.0000
12:2922261:GGTA:G	acceptor_gain	1.0000
12:2922261:GGTAT:G	acceptor_gain	1.0000
12:2922385:A:T	donor_gain	1.0000
12:2922398:GCATG:G	donor_gain	1.0000
12:2922403:G:GG	donor_gain	1.0000
12:2922403:GTGAG:G	donor_loss	1.0000
12:2922404:T:TC	donor_loss	1.0000
12:2930244:CTA:C	acceptor_loss	1.0000
12:2930245:TA:T	acceptor_loss	1.0000
12:2930246:A:AG	acceptor_gain	1.0000
12:2930246:AGAT:A	acceptor_loss	1.0000

AlphaMissense

2929 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:2934469:T:C	F278L	1.000
12:2934471:T:A	F278L	1.000
12:2934471:T:G	F278L	1.000
12:2938225:T:C	F379L	1.000
12:2938227:C:A	F379L	1.000
12:2938227:C:G	F379L	1.000
12:2938260:C:A	N390K	1.000
12:2938260:C:G	N390K	1.000
12:2939355:T:C	F414L	1.000
12:2939357:C:A	F414L	1.000
12:2939357:C:G	F414L	1.000
12:2931167:G:C	R208P	0.999
12:2933521:G:A	G267D	0.999
12:2933527:T:C	L269P	0.999
12:2937662:G:T	R319M	0.999
12:2938187:C:A	P366H	0.999
12:2938192:T:A	W368R	0.999
12:2938192:T:C	W368R	0.999
12:2938220:T:A	L377H	0.999
12:2938220:T:C	L377P	0.999
12:2938226:T:C	F379S	0.999
12:2938226:T:G	F379C	0.999
12:2938257:G:C	K389N	0.999
12:2938257:G:T	K389N	0.999
12:2938258:A:C	N390H	0.999
12:2938259:A:C	N390T	0.999
12:2938259:A:T	N390I	0.999
12:2938261:T:C	F391L	0.999
12:2938263:C:A	F391L	0.999
12:2938263:C:G	F391L	0.999

dbSNP variants (sampled 300 via entrez): RS1000054094 (12:2925477 G>T), RS1000090821 (12:2932115 C>T), RS1000100380 (12:2894682 T>A), RS1000261461 (12:2894362 C>T), RS1000298001 (12:2937095 ACT>A), RS1000318318 (12:2914069 T>G), RS1000400787 (12:2905416 C>G,T), RS1000430438 (12:2908520 G>A), RS1000552200 (12:2903579 A>C,G), RS1000554806 (12:2911118 T>C), RS1000590283 (12:2931838 C>T), RS1000593894 (12:2940386 T>C), RS1000690865 (12:2935138 G>T), RS1000738117 (12:2898334 T>C), RS1000745313 (12:2899708 A>C,G)

Disease associations

OMIM: gene MIM:604730 | disease phenotypes: MIM:619902

GenCC curated gene-disease

Disease	Classification	Inheritance
hepatorenocardiac degenerative fibrosis	Strong	Autosomal recessive
ciliopathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ciliopathy	Strong	AR

Mondo (2): hepatorenocardiac degenerative fibrosis (MONDO:0859254), ciliopathy (MONDO:0005308)

Orphanet (0):

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000105	Enlarged kidney
HP:0000107	Renal cyst
HP:0000952	Jaundice
HP:0001394	Cirrhosis
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001639	Hypertrophic cardiomyopathy
HP:0001971	Hypersplenism
HP:0002480	Hepatic encephalopathy
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004719	Hyperechogenic kidneys
HP:0005565	Reduced renal corticomedullary differentiation
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0012852	Hepatic bridging fibrosis
HP:0032622	Tubular luminal dilatation
HP:0032948	Renal interstitial fibrosis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST90002390_45	Mean corpuscular hemoglobin	5.000000e-13
GCST90002392_366	Mean corpuscular volume	1.000000e-15
GCST90002396_512	Mean reticulocyte volume	1.000000e-11
GCST90002397_410	Mean spheric corpuscular volume	1.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Tretinoin	decreases expression	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
geraniol	increases expression	1
kojic acid	decreases expression	1
sodium arsenite	decreases expression, increases abundance, affects cotreatment	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
tamibarotene	affects expression	1
K 7174	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	affects response to substance	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arbutin	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Carmustine	affects response to substance	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Selenium	affects cotreatment, decreases expression	1
Smoke	increases abundance, increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Vitamin E	affects cotreatment, decreases expression	1
Zinc	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)