CDKAL1

Summary

CDKAL1 (CDKAL1 threonylcarbamoyladenosine tRNA methylthiotransferase, HGNC:21050) is a protein-coding gene on chromosome 6p22.3, encoding Threonylcarbamoyladenosine tRNA methylthiotransferase (Q5VV42). Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.

The protein encoded by this gene is a member of the methylthiotransferase family. The function of this gene is not known. Genome-wide association studies have linked single nucleotide polymorphisms in an intron of this gene with susceptibilty to type 2 diabetes.

Source: NCBI Gene 54901 — RefSeq curated summary.

At a glance

• GWAS associations: 123
• Clinical variants (ClinVar): 116 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_017774

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21050
Approved symbol	CDKAL1
Name	CDKAL1 threonylcarbamoyladenosine tRNA methylthiotransferase
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20342
Ensembl gene	ENSG00000145996
Ensembl biotype	protein_coding
OMIM	611259
Entrez	54901

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000274695, ENST00000378610, ENST00000476517, ENST00000613575, ENST00000879569, ENST00000879570, ENST00000879571, ENST00000914206, ENST00000914207, ENST00000946780, ENST00000946781, ENST00000946782, ENST00000946783

RefSeq mRNA: 1 — MANE Select: NM_017774 NM_017774

CCDS: CCDS4546

Canonical transcript exons

ENST00000274695 — 16 exons

Exon	Start	End
ENSE00001356405	20535351	20535394
ENSE00001478169	20534457	20534574
ENSE00003520143	21201110	21201274
ENSE00003889148	20739519	20739615
ENSE00003889666	20846075	20846178
ENSE00003890864	21230848	21232404
ENSE00003891294	20548593	20548705
ENSE00003891455	20649293	20649377
ENSE00003893032	20781145	20781265
ENSE00003893256	20758595	20758643
ENSE00003893317	20546346	20546523
ENSE00003894514	21065048	21065228
ENSE00003894779	21000227	21000372
ENSE00003894894	21198021	21198104
ENSE00003895326	20955419	20955585
ENSE00003896136	21108401	21108463

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 92.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.7611 / max 525.8328, expressed in 1803 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66256	26.1281	1800
66257	1.4182	770
66290	0.4429	77
66258	0.4041	188
66289	0.3156	101
66279	0.0283	6
66291	0.0238	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.18	gold quality
calcaneal tendon	UBERON:0003701	90.38	gold quality
ganglionic eminence	UBERON:0004023	88.27	gold quality
ventricular zone	UBERON:0003053	87.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.52	gold quality
cortical plate	UBERON:0005343	82.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.61	gold quality
adrenal tissue	UBERON:0018303	81.54	gold quality
muscle of leg	UBERON:0001383	80.80	gold quality
gastrocnemius	UBERON:0001388	80.23	gold quality
embryo	UBERON:0000922	79.71	gold quality
colonic epithelium	UBERON:0000397	79.18	gold quality
stromal cell of endometrium	CL:0002255	79.14	gold quality
left ovary	UBERON:0002119	79.03	gold quality
islet of Langerhans	UBERON:0000006	78.88	gold quality
popliteal artery	UBERON:0002250	78.67	gold quality
tibial artery	UBERON:0007610	78.65	gold quality
skin of leg	UBERON:0001511	78.45	gold quality
monocyte	CL:0000576	78.40	gold quality
leukocyte	CL:0000738	78.39	gold quality
mononuclear cell	CL:0000842	78.14	gold quality
skin of abdomen	UBERON:0001416	78.07	gold quality
rectum	UBERON:0001052	78.01	gold quality
right ovary	UBERON:0002118	77.97	gold quality
sural nerve	UBERON:0015488	77.93	gold quality
ovary	UBERON:0000992	77.88	gold quality
right uterine tube	UBERON:0001302	77.81	gold quality
body of pancreas	UBERON:0001150	77.50	gold quality
body of uterus	UBERON:0009853	77.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.71
E-CURD-10	no	101.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting CDKAL1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-1273H-5P	99.77	66.32	2471

Literature-anchored findings (GeneRIF, showing 40)

• Single Nucleotide polymorphism in CDK5 regulatory subunit associated protein 1-like 1 is associated with type 2 diabetes (PMID:17460697)
• CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. (PMID:17804762)
• The association of 6 loci with type 2 diabetes risk in Japanese patients is reported. (PMID:18162508)
• Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. (PMID:18264689)
• CDKAL1 is likely to increase the risk of type 2 diabetes by impairing insulin secretion. (PMID:18285412)
• Data confirmed the associations of single nucleotide polymorphisms in CDKAL1 with risk for type 2 diabetes in Asians. (PMID:18469204)
• One SNP, rs7754840 in the CDKAL1 gene, presented a significantly stronger effect in the Ashkenazi Jewish population as compared to the general Caucasian population for type 2 diabetes susceptibility. (PMID:18516622)
• Gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. (PMID:18597214)
• Variants of CDKAL1 and IGF2BP2 attenuate the first phase of glucose-stimulated insulin secretion but show no effect on the second phase of insulin secretion in hyperglycmia and type 2 diabetes. (PMID:18618095)
• The results indicate that in Chinese Hans, common variants in CDKAL1 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction. (PMID:18633108)
• Study show that polymorphisms in CDKAL1 were associated with type 2 diabetes risk in the studied population. (PMID:18694974)
• The underlying mechanisms linking CDKAL1, glutamate decarboxylase, and insulin secretion are unclear. A recent case-control study found no association of variation in CDKAL1 with type 1 diabete.s (PMID:18753662)
• Positive association between single nucleotide polymorphisms in this gene with type 2 diabetes in Han Chinese. (PMID:18766326)
• ADAM33, CDKAL1, and PTPN22 may be true psoriasis-risk genes (PMID:18923449)
• Single nucleotide polymorphism in CDKAL1 is associated with type 2 diabetes. (PMID:18991055)
• Data show that SNPs in CDKAL1 did not confer a significant risk for type 2 diabetes in Pima Indians. (PMID:19008344)
• Type 2 diabetes susceptibility of CDKAL1 was confirmed in Japanese. (PMID:19033397)
• The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (PMID:19422935)
• CDKAL1 alleles may confer susceptibility to clinically distinct disorders through differential effects on disease-specific cell types. (PMID:19587699)
• Association between lower birth weight and type 2 diabetes risk-conferring alleles at the CDKAL1 locus. (PMID:19592620)
• Single nucleotide polymorphisms in CDKAL1 have no association with polycystic ovary syndrome or related clinical features in Chinese women. (PMID:19718565)
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population (PMID:19862325)
• Studies identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities. (PMID:20161779)
• Type 2 diabetes susceptibility alleles at CDKAL1 are associated with low body mass index at 8 years in children who were born large for gestational age. (PMID:20460429)
• Data report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. (PMID:20490451)
• there are significant associations between CDKAL1 polymorphisms and type 2 diabetes [meta-analysis] (PMID:20568056)
• Interaction between the CDKAL1 polymorphism and dietary energy intake influences the dysglycemic phenotype leading to MetS, possibly through impaired insulin secretion. The CDKAL1 polymorphism may be a marker for MetS in the Japanese population. (PMID:20847106)
• Single nucleotide polymorphism (SNP) analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of type 2 diabetes mellitus in females, but not in males. (PMID:21368910)
• no relationship of CDKAL1 and KCNQ1 polymorphisms to the earlier onset of type 2 diabetes was observed (PMID:21416855)
• CDKAL1 is involved in the pathogenesis of T2 diabetes through impaired beta-cell function. (PMID:21611789)
• A significant association between Type 2 Diabetes Mellitus, an increased Fasting Plasma Glucose and rs7754840 at CDKAL1 in lean Han Chinese. (PMID:21643948)
• Variants in cdkal1 gene have been reproducibly associated with decreased first-phase insulin secretion and development of type 2 diabetes. (PMID:21908934)
• Six SNP(rs7754840 in CDKAL1, rs391300 in SRR, rs2383208 in CDKN2A/2B, rs4402960 in IGF2BP2, rs10830963 in MTNR1B, rs4607517 in GCK)risk alleles of type 2 diabetes were associated with GDM in pregnant Chinese women. (PMID:22096510)
• CDKAL1 rs7754840 and rs7756992, but not CDKN2A/2B rs10811661, are associated with T2DM in Lebanese. (PMID:22119613)
• CDKAL1 might influence the level of glycosylated hemoglobin (PMID:22290723)
• Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. (PMID:22344221)
• Our findings indicated that genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in Chinese population. (PMID:22437209)
• None of the 12 SNPs in the six genes (KCNJ11, TCF7L2, SLC30A8, HHEX, FTO and CDKAL1) uncovered in the genome-wide association studies were associated with polycystic ovary syndrome. (PMID:22443257)
• The associations between SNPs of TCF7L2, CDKAL1, SLC30A8 and HHEX and the development of DR and DN. (PMID:22487833)
• rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. (PMID:22923468)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkal1	ENSDARG00000104848
danio_rerio		ENSDARG00000110572
mus_musculus	Cdkal1	ENSMUSG00000006191
rattus_norvegicus	LOC120093069	ENSRNOG00000018381
drosophila_melanogaster	CG6550	FBGN0034214
caenorhabditis_elegans	Y92H12BL.1	WBGENE00022363

Paralogs (1): CDK5RAP1 (ENSG00000101391)

Protein

Protein identifiers

Threonylcarbamoyladenosine tRNA methylthiotransferase — Q5VV42 (reviewed: Q5VV42)

Alternative names: CDK5 regulatory subunit-associated protein 1-like 1, tRNA-t(6)A37 methylthiotransferase

All UniProt accessions (1): Q5VV42

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in pancreatic islets.

Disease relevance. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Cofactor. Binds 2 [4Fe-4S] clusters. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.

Similarity. Belongs to the methylthiotransferase family. CDKAL1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5VV42-1	1	yes
Q5VV42-2	2
Q5VV42-3	3

RefSeq proteins (1): NP_060244* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002792	TRAM_dom	Domain
IPR005839	Methylthiotransferase	Family
IPR006466	MiaB-like_arc_euk	Family
IPR006638	Elp3/MiaA/NifB-like_rSAM	Domain
IPR007197	rSAM	Domain
IPR013848	Methylthiotransferase_N	Domain
IPR020612	Methylthiotransferase_CS	Conserved_site
IPR023404	rSAM_horseshoe	Homologous_superfamily
IPR038135	Methylthiotransferase_N_sf	Homologous_superfamily
IPR058240	rSAM_sf	Homologous_superfamily

Pfam: PF00919, PF01938, PF04055

Catalyzed reactions (Rhea), 1 shown:

• N(6)-L-threonylcarbamoyladenosine(37) in tRNA + (sulfur carrier)-SH + AH2 + 2 S-adenosyl-L-methionine = 2-methylsulfanyl-N(6)-L-threonylcarbamoyladenosine(37) in tRNA + (sulfur carrier)-H + 5’-deoxyadenosine + L-methionine + A + S-adenosyl-L-homocysteine + 2 H(+) (RHEA:37075)

UniProt features (20 total): binding site 6, splice variant 4, modified residue 3, domain 3, chain 1, transmembrane region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VV42-F1	82.72	0.70

Functional residue map

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

Ligand- & substrate-binding residues (6): 221; 73; 109; 138; 214; 218

Post-translational modifications (3): 53, 122, 499

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 134 (showing top): TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_TRANSLATION, GOBP_RNA_MODIFICATION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, YRTCANNRCGC_UNKNOWN, FISCHER_DREAM_TARGETS, NOUZOVA_TRETINOIN_AND_H4_ACETYLATION, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOBP_TRNA_MODIFICATION, GOCC_ROUGH_ENDOPLASMIC_RETICULUM

GO Biological Process (5): tRNA methylthiolation (GO:0035600), maintenance of translational fidelity (GO:1990145), tRNA modification (GO:0006400), tRNA processing (GO:0008033), biological_process (GO:0008150)

GO Molecular Function (8): tRNA (N(6)-L-threonylcarbamoyladenosine(37)-C(2))-methylthiotransferase activity (GO:0035598), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), methylthiotransferase activity (GO:0035596), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), rough endoplasmic reticulum (GO:0005791), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA modification	1
translation	1
macromolecule biosynthetic process	1
tRNA processing	1
RNA modification	1
RNA processing	1
tRNA metabolic process	1
methylthiotransferase activity	1
tRNA methylthiolation	1
catalytic activity, acting on a tRNA	1
cation binding	1
iron-sulfur cluster binding	1
molecular_function	1
binding	1
catalytic activity	1
alkylthioltransferase activity	1
metal cluster binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKAL1	SLC30A8	Q8IWU4	927
CDKAL1	HHEX	Q03014	925
CDKAL1	IGF2BP2	Q9Y6M1	898
CDKAL1	TCF7L2	Q9NQB0	885
CDKAL1	FTO	Q9C0B1	868
CDKAL1	KCNJ11	Q14654	857
CDKAL1	KCNQ1	P51787	834
CDKAL1	MTNR1B	P49286	801
CDKAL1	ADAMTS9	Q9P2N4	783
CDKAL1	TSPAN8	P19075	782
CDKAL1	CDC123	O75794	780
CDKAL1	JAZF1	Q86VZ6	762
CDKAL1	ADCY5	O95622	731
CDKAL1	WFS1	O76024	729
CDKAL1	CDKN2B	P42772	712

IntAct

135 interactions, top by confidence:

A	B	Type	Score
MMS19	CIAO1	psi-mi:“MI:0914”(association)	0.910
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MMS19	ERCC2	psi-mi:“MI:0914”(association)	0.690
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
LCK	CDKAL1	psi-mi:“MI:0915”(physical association)	0.560
CDKAL1	LCK	psi-mi:“MI:0915”(physical association)	0.560
CDKAL1	WFS1	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	CDKAL1	psi-mi:“MI:0915”(physical association)	0.560
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
EVA1C	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
UPRT	SERPINB4	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
Mms19	CIAO1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (321): CDKAL1 (Two-hybrid), CDKAL1 (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CDKAL1 (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), TTYH3 (Affinity Capture-MS), BPIFB1 (Affinity Capture-MS)

ESM2 similar proteins: A2XDA1, C3VEP9, C3VEQ0, G4LTX4, O04397, O18756, O24163, O48741, O49901, O81770, O94923, P09559, P21218, P25697, P26294, P26302, P27774, P28553, P28554, P29273, P49086, P55826, P80093, Q01289, Q07356, Q0DUI8, Q2VEX9, Q38893, Q40406, Q42536, Q42850, Q43415, Q43503, Q52QW2, Q52QW3, Q5IH13, Q5IH14, Q5VV42, Q6STH5, Q7XTG7

Diamond homologs: A0JUY6, A0KTX4, A0L7K3, A1JQA3, A1R550, A1S8S1, A1U494, A3D7M8, A3DDI9, A3QH41, A4TNY6, A4XL48, A5CSL5, A5D2K1, A5FPV2, A5G670, A5IJD4, A5UUG7, A6U5H0, A6V0C9, A6VZE1, A6W848, A7FKU9, A7HK86, A8F716, A8FZ02, A8H7B6, A8LSE7, A9HZZ2, A9R6X8, B0K1A1, B0K9L4, B0TR38, B1JG95, B1KDV4, B1L8F3, B2A3X6, B2JD88, B2K896, B2RKG6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDKAL1	“up-regulates quantity”	tRNA(Lys)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 156 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	27.6×	1e-04
DAP12 signaling	5	19.6×	3e-04
Signaling by SCF-KIT	5	13.2×	1e-03
R-HSA-425393	5	6.9×	8e-03
Constitutive Signaling by Aberrant PI3K in Cancer	5	6.8×	9e-03
SLC-mediated transmembrane transport	10	6.3×	3e-04
Transport of small molecules	13	3.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	78
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
226276	GRCh37/hg19 6p22.3(chr6:20884837-21082258)	Likely pathogenic

SpliceAI

6896 predictions. Top by Δscore:

Variant	Effect	Δscore
6:20535200:G:GG	donor_gain	1.0000
6:20546337:A:AG	acceptor_gain	1.0000
6:20546337:AT:A	acceptor_gain	1.0000
6:20546337:ATGT:A	acceptor_gain	1.0000
6:20546340:T:TA	acceptor_gain	1.0000
6:20546345:GA:G	acceptor_gain	1.0000
6:20546345:GAGA:G	acceptor_gain	1.0000
6:20546345:GAGAA:G	acceptor_gain	1.0000
6:20546523:GGTAA:G	donor_loss	1.0000
6:20546524:G:GG	donor_gain	1.0000
6:20546524:GTAA:G	donor_loss	1.0000
6:20546525:T:A	donor_loss	1.0000
6:20548577:ATT:A	acceptor_gain	1.0000
6:20548579:T:A	acceptor_gain	1.0000
6:20548592:GC:G	acceptor_gain	1.0000
6:20548592:GCA:G	acceptor_gain	1.0000
6:20548592:GCACT:G	acceptor_gain	1.0000
6:20548701:TACAG:T	donor_loss	1.0000
6:20548702:ACAGG:A	donor_loss	1.0000
6:20548703:CAG:C	donor_loss	1.0000
6:20548704:AGGTA:A	donor_loss	1.0000
6:20548705:GGT:G	donor_loss	1.0000
6:20548706:GTAAT:G	donor_loss	1.0000
6:20548707:T:G	donor_loss	1.0000
6:20597980:GGAT:G	donor_gain	1.0000
6:20597981:GATG:G	donor_gain	1.0000
6:20649288:A:AG	acceptor_gain	1.0000
6:20649291:A:AG	acceptor_gain	1.0000
6:20649292:G:GG	acceptor_gain	1.0000
6:20649292:GA:G	acceptor_gain	1.0000

AlphaMissense

3822 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:20548633:G:C	G72R	1.000
6:20548636:T:A	C73S	1.000
6:20548636:T:C	C73R	1.000
6:20548637:G:A	C73Y	1.000
6:20548637:G:C	C73S	1.000
6:20548638:T:G	C73W	1.000
6:20548647:T:A	N76K	1.000
6:20548647:T:G	N76K	1.000
6:20649328:A:C	S108R	1.000
6:20649330:T:A	S108R	1.000
6:20649330:T:G	S108R	1.000
6:20649331:T:A	C109S	1.000
6:20649331:T:C	C109R	1.000
6:20649332:G:A	C109Y	1.000
6:20649332:G:C	C109S	1.000
6:20649332:G:T	C109F	1.000
6:20649333:C:G	C109W	1.000
6:20649340:A:G	K112E	1.000
6:20649342:A:C	K112N	1.000
6:20649342:A:T	K112N	1.000
6:20739557:G:A	G137E	1.000
6:20739559:T:A	C138S	1.000
6:20739559:T:C	C138R	1.000
6:20739560:G:A	C138Y	1.000
6:20739560:G:C	C138S	1.000
6:20739561:C:G	C138W	1.000
6:20739604:A:C	S153R	1.000
6:20739606:T:A	S153R	1.000
6:20739606:T:G	S153R	1.000
6:20758611:G:C	R162P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002750 (6:20743625 G>A,T), RS1000003030 (6:21088652 A>C,G), RS1000004245 (6:20885782 C>T), RS1000014699 (6:20702934 G>A,C), RS1000017055 (6:21059703 C>A,T), RS1000021546 (6:20873061 C>G,T), RS1000026107 (6:20548299 A>G), RS1000028876 (6:20999909 A>G), RS1000033389 (6:21113905 T>A), RS1000037470 (6:21085179 T>A), RS1000044033 (6:21219728 G>A), RS1000044751 (6:20650034 T>C,G), RS1000053640 (6:20633318 C>G), RS1000055776 (6:20843728 A>G), RS1000061692 (6:20918295 C>T)

Disease associations

OMIM: gene MIM:611259 | disease phenotypes: MIM:125853

GenCC curated gene-disease

Mondo (2): type 2 diabetes mellitus (MONDO:0005148), obesity disorder (MONDO:0011122)

Orphanet (2): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001513	Obesity

GWAS associations

123 associations (top):

Study	Trait	p-value
GCST000024_8	Type 2 diabetes	4.000000e-11
GCST000025_2	Type 2 diabetes	1.000000e-08
GCST000027_3	Type 2 diabetes	8.000000e-09
GCST000028_6	Type 2 diabetes	4.000000e-11
GCST000047_4	Type 2 diabetes	3.000000e-07
GCST000167_12	Type 2 diabetes	1.000000e-11
GCST000207_17	Crohn’s disease	9.000000e-10
GCST000221_2	Type 2 diabetes	3.000000e-10
GCST000383_1	Type 2 diabetes	7.000000e-20
GCST000478_4	Type 2 diabetes	2.000000e-12
GCST000712_23	Type 2 diabetes	2.000000e-22
GCST000879_60	Crohn’s disease	1.000000e-08
GCST000908_2	Ileal carcinoids	8.000000e-06
GCST001033_4	Type 2 diabetes	9.000000e-06
GCST001375_3	Diabetes (gestational)	7.000000e-16
GCST001393_1	Glycated hemoglobin levels	1.000000e-11
GCST001415_2	Body mass index	2.000000e-11
GCST001416_4	Body mass index (SNP x SNP interaction)	1.000000e-11
GCST001550_12	Type 2 diabetes	7.000000e-10
GCST001550_8	Type 2 diabetes	6.000000e-11
GCST001666_9	Type 2 diabetes	7.000000e-10
GCST001758_5	Birth weight	2.000000e-18
GCST001762_831	Obesity-related traits	8.000000e-06
GCST001965_8	Glycemic traits	3.000000e-19
GCST002128_4	Type 2 diabetes	2.000000e-13
GCST002243_5	Bladder cancer	7.000000e-07
GCST002352_32	Type 2 diabetes	2.000000e-26
GCST002390_10	Glycated hemoglobin levels	4.000000e-08
GCST002461_20	Body mass index	5.000000e-13
GCST002586_7	Fasting plasma glucose	9.000000e-10

EFO canonical traits (35, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement
EFO:0004340	body mass index
EFO:0004344	birth weight
EFO:0004338	body weight
EFO:0006831	acute insulin response measurement
EFO:0004337	intelligence
EFO:1001494	psoriasis vulgaris
EFO:0004847	age at onset
EFO:0007965	response to combination chemotherapy
EFO:0008000	peak insulin response measurement
EFO:0008473	insulin response measurement
EFO:0004471	insulin sensitivity measurement
EFO:0004467	insulin measurement
EFO:0006832	disposition index measurement
EFO:0009132	cholesterol efflux capacity measurement
EFO:0007785	femoral neck bone mineral density
EFO:0007701	spine bone mineral density
EFO:0004468	glucose measurement
EFO:0006335	systolic blood pressure
EFO:0003924	hair color
EFO:0005763	pulse pressure measurement
EFO:0009924	Drugs used in diabetes use measurement
EFO:0004531	urate measurement
EFO:0010273	thoracic aortic calcification measurement
EFO:0010475	deoxycholate measurement
EFO:0007629	hemoglobin A1 measurement
EFO:0004632	nevus count
EFO:0006842	diabetes mellitus biomarker
EFO:0000195	metabolic syndrome
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196100 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6908425	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis
rs7754840	Efficacy	3	Dipeptidyl peptidase 4 (DPP-4) inhibitors	Diabetes Mellitus
rs7756992	Efficacy	3	Dipeptidyl peptidase 4 (DPP-4) inhibitors	Diabetes Mellitus

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7754840	CDKAL1	3	2.75	1	Dipeptidyl peptidase 4 (DPP-4) inhibitors
rs7756992	CDKAL1	3	3.25	1	Dipeptidyl peptidase 4 (DPP-4) inhibitors
rs6908425	CDKAL1	3	2.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	5
Aflatoxin B1	affects expression, decreases expression, increases methylation	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Cisplatin	decreases expression, affects cotreatment	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
jinfukang	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Hydrogen Peroxide	decreases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6158956	Binding	Rescue of mistranslation activity in CDKAL1 (unknown origin) extracted from Escherichia coli harboring MIaB deficient at 10 uM incubated for 1 hr by dual luciferase assay	Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus