TLL1

Summary

TLL1 (tolloid like 1, HGNC:11843) is a protein-coding gene on chromosome 4q32.3, encoding Tolloid-like protein 1 (O43897). Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase.

This gene encodes an astacin-like, zinc-dependent, metalloprotease that belongs to the peptidase M12A family. This protease processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Studies in mice suggest that this gene plays multiple roles in the development of mammalian heart, and is essential for the formation of the interventricular septum. Allelic variants of this gene are associated with atrial septal defect type 6. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrial septal defect 6 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 203 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes
• MANE Select transcript: NM_012464

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11843
Approved symbol	TLL1
Name	tolloid like 1
Location	4q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000038295
Ensembl biotype	protein_coding
OMIM	606742
Entrez	7092

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 nonsense_mediated_decay

ENST00000061240, ENST00000504560, ENST00000506144, ENST00000507499, ENST00000509505, ENST00000513213

RefSeq mRNA: 2 — MANE Select: NM_012464 NM_001204760, NM_012464

CCDS: CCDS3811, CCDS56342

Canonical transcript exons

ENST00000061240 — 21 exons

Exon	Start	End
ENSE00001248950	166100742	166104457
ENSE00001248957	165873237	165874073
ENSE00003485218	166007943	166008048
ENSE00003488835	166077903	166078030
ENSE00003496842	166014436	166014560
ENSE00003499879	166060028	166060188
ENSE00003505006	166003391	166003569
ENSE00003524679	166091128	166091341
ENSE00003525165	166074878	166075003
ENSE00003529412	165989381	165989491
ENSE00003556048	165992804	165992884
ENSE00003568273	166039339	166039441
ENSE00003618486	166025316	166025431
ENSE00003623294	166065683	166065863
ENSE00003634692	166057184	166057309
ENSE00003638809	165994381	165994533
ENSE00003656455	166055076	166055271
ENSE00003656733	166043274	166043419
ENSE00003660814	166099277	166099527
ENSE00003670109	166042027	166042143
ENSE00003788931	165995061	165995178

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 84.49.

FANTOM5 (CAGE): breadth broad, TPM avg 1.1845 / max 161.0757, expressed in 399 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50471	0.3457	159
50477	0.2178	75
203411	0.1980	92
50476	0.0982	34
203410	0.0938	44
50472	0.0824	17
50475	0.0487	9
203412	0.0403	12
50470	0.0277	13
50473	0.0208	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	84.49	gold quality
buccal mucosa cell	CL:0002336	82.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.84	gold quality
cerebellar cortex	UBERON:0002129	75.26	gold quality
cerebellar hemisphere	UBERON:0002245	75.21	gold quality
colonic epithelium	UBERON:0000397	74.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.67	gold quality
calcaneal tendon	UBERON:0003701	73.60	gold quality
cerebellum	UBERON:0002037	73.29	gold quality
gall bladder	UBERON:0002110	71.56	gold quality
omental fat pad	UBERON:0010414	69.37	gold quality
peritoneum	UBERON:0002358	69.29	gold quality
oocyte	CL:0000023	68.66	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.80	gold quality
smooth muscle tissue	UBERON:0001135	66.53	gold quality
lower esophagus	UBERON:0013473	66.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	66.13	gold quality
subcutaneous adipose tissue	UBERON:0002190	65.90	gold quality
ectocervix	UBERON:0012249	65.58	gold quality
left uterine tube	UBERON:0001303	64.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	64.19	gold quality
skin of abdomen	UBERON:0001416	63.70	gold quality
endocervix	UBERON:0000458	63.65	gold quality
rectum	UBERON:0001052	63.53	gold quality
left coronary artery	UBERON:0001626	63.33	gold quality
body of uterus	UBERON:0009853	62.44	gold quality
islet of Langerhans	UBERON:0000006	62.23	gold quality
lymph node	UBERON:0000029	61.86	gold quality
coronary artery	UBERON:0001621	61.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.53
E-HCAD-30	no	358.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5

miRNA regulators (miRDB)

49 targeting TLL1, 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-5692A	100.00	74.40	6850
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-1825	99.72	68.11	1089

Literature-anchored findings (GeneRIF, showing 22)

• tolloid-like 1 binds procollagen C-proteinase enhancer protein 1 and differs from bone morphogenetic protein 1 in the functional roles of homologous protein domains (PMID:16507574)
• The crystal structures of the protease domains of human BMP-1 and the closely related Tolloid-like protease 1 (TLL-1), are reported. (PMID:18824173)
• Mutations in mammalian tolloid-like 1 gene detected in adult patients with Atrial septal defect (PMID:18830233)
• These results indicate that the hypoxia responsive motif is directly involved in the activation of the mTll-1 transcription under hypoxic conditions. (PMID:19723501)
• Data demonstrate that TLL-1, which has intermediate activity, forms a calcium-ion dependent dimer with monomers stacked side-by-side. (PMID:20043912)
• We identified a variant in a single PPAR pathway gene, TLL1, that is associated with the extent of coronary artery disease independently of clinical predictors, specifically in patients with type 2 diabetes mellitus. (PMID:21911782)
• TLL-1 gene mutation with an insertion mutation of base A in exon 10 is common in Chinese patients with sporadic congenital heart diseases. (PMID:22883091)
• This study identified TLL1 as a new susceptibility gene for PTSD. (PMID:23726511)
• This SNP [TLL1 gene ]could not be confirmed as a risk factor for CHD [coronary heart disease]in T2DM [type-2 Diabetes mellitus]patients (PMID:25233961)
• Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008). (PMID:28163062)
• The results of this large-scale cohort study imply that the combination of the PNPLA3 and TLL1 genotype may be associated with an increased risk of advanced fibrosis among patients with nonalcoholic fatty liver disease. (PMID:28744823)
• TLL-1 genetic variants determined fibrotic improvement in chronic hepatitis C with curative antivirals, particularly in patients with mild liver disease. (PMID:30305682)
• The TLL1 variant was independently associated with hepatocellular carcinoma after hepatitis C virus eradication by interferon-free regimen; it might be involved in hepatic fibrogenesis and thereby carcinogenesis (PMID:30382363)
• Mutations detected in TLL1 of ASD6 patients altered its metalloendopeptidase activity. (PMID:30538173)
• The incidence of hepatocellular carcinoma was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian hepatitis C cirrhotics treated with direct-acting antiviral, TLL1 variants do not predict hepatocellular carcinoma development. (PMID:31177595)
• Proteinase bone morphogenetic protein 1, but not tolloid-like 1, plays a dominant role in maintaining periodontal homeostasis. (PMID:33169406)
• Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease. (PMID:33306709)
• Chitinase 3-like-1, Tolloid-like protein 1, and intergenic gene polymorphisms are predictors for hepatocellular carcinoma development after hepatitis C virus eradication by direct-acting antivirals. (PMID:33347699)
• Characterization of tolloid-mediated cleavage of the GDF8 procomplex. (PMID:33876824)
• Association between Interferon-Lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 Variant Polymorphisms with the Course and Outcome of SARS-CoV-2 Patients. (PMID:34071309)
• Klebsiella pneumoniae activates the TGF-beta signaling pathway to adhere to and invade intestinal epithelial cells via enhancing TLL1 expression. (PMID:36087399)
• Assessment of TLL1 variant and risk of hepatocellular carcinoma in Latin Americans and Europeans. (PMID:37981236)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tll1	ENSDARG00000037429
mus_musculus	Tll1	ENSMUSG00000053626
rattus_norvegicus	Tll1	ENSRNOG00000033528
drosophila_melanogaster	tld	FBGN0003719

Paralogs (35): NRXN3 (ENSG00000021645), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Tolloid-like protein 1 — O43897 (reviewed: O43897)

All UniProt accessions (5): D6RAK5, D6RBI6, D6RCE0, E9PD25, O43897

UniProt curated annotations — full annotation on UniProt →

Function. Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.

Subcellular location. Secreted.

Disease relevance. Atrial septal defect 6 (ASD6) [MIM:613087] A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Isoforms (2)

UniProt ID	Names	Canonical?
O43897-1	1	yes
O43897-2	2

RefSeq proteins (2): NP_001191689, NP_036596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000859	CUB_dom	Domain
IPR001506	Peptidase_M12A	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR006026	Peptidase_Metallo	Domain
IPR015446	BMP_1/tolloid-like	Family
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034036	ZnMP_TLD/BMP1	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily

Pfam: PF00431, PF01400, PF14670

UniProt features (66 total): disulfide bond 19, helix 10, domain 8, strand 7, sequence variant 5, glycosylation site 4, binding site 3, sequence conflict 3, splice variant 2, signal peptide 1, propeptide 1, active site 1, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3EDI	X-RAY DIFFRACTION	1.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43897-F1	80.64	0.42

Functional residue map

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

Catalytic / active sites (1): 241

Ligand- & substrate-binding residues (3): 240; 244; 250

Disulfide bonds (19): 190–346, 210–232, 212–213, 349–375, 402–424, 462–488, 515–537, 578–590, 586–599, 601–614, 618–644, 671–693, 734–745, 741–754, 756–769, 774–800, 827–849, 887–917, 944–966

Glycosylation sites (4): 169, 359, 390, 626

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-2214320	Anchoring fibril formation
R-HSA-2243919	Crosslinking of collagen fibrils

MSigDB gene sets: 303 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, MORF_ITGA2, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, AP1_01, BENPORATH_ES_WITH_H3K27ME3, chr4q32, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, USF_C, MORF_RAD51L3

GO Biological Process (6): skeletal system development (GO:0001501), dorsal/ventral pattern formation (GO:0009953), protein processing (GO:0016485), cell differentiation (GO:0030154), collagen fibril organization (GO:0030199), proteolysis (GO:0006508)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Assembly of collagen fibrils and other multimeric structures	2
Extracellular matrix organization	1
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase activity	2
cellular anatomical structure	2
system development	1
regionalization	1
proteolysis	1
protein maturation	1
cellular developmental process	1
extracellular matrix organization	1
protein metabolic process	1
metallopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
transition metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLL1	CHRD	Q9H2X0	895
TLL1	TBX20	Q9UMR3	703
TLL1	LAMA3	Q16787	549
TLL1	LAMC2	Q13753	547
TLL1	PRTFDC1	Q9NRG1	542
TLL1	LAMA4	Q16363	497
TLL1	ACTC1	P04270	496
TLL1	CSH1	P01243	491
TLL1	APP	P05067	480
TLL1	CSH1	P01243	470
TLL1	MBL2	P11226	469
TLL1	GATA4	P43694	458
TLL1	MYH6	P13533	441
TLL1	DEPDC5	O75140	424
TLL1	MFAP5	Q13361	424

IntAct

9 interactions, top by confidence:

A	B	Type	Score
	TLL1	psi-mi:“MI:0407”(direct interaction)	0.540
TLL1	MBL2	psi-mi:“MI:0407”(direct interaction)	0.540
BMP1	TLL1	psi-mi:“MI:0914”(association)	0.530
TLL1	C1R	psi-mi:“MI:0915”(physical association)	0.400
TLL1	MASP2	psi-mi:“MI:0915”(physical association)	0.400
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): TLL1 (Affinity Capture-MS), TLL1 (Affinity Capture-RNA), TLL1 (Affinity Capture-MS), TLL1 (Affinity Capture-RNA), TLL1 (Affinity Capture-MS), TLL1 (Proximity Label-MS), TLL1 (Affinity Capture-MS), KLF9 (Cross-Linking-MS (XL-MS)), TLL1 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A0C5PRQ1, A6H737, A8Q2D1, D5FM34, D5FM37, E1C3U7, K7Z9Q9, O17264, O35548, O43897, O54732, O57460, O77636, P25723, P50281, P51511, P51512, P55114, P98060, P98069, P98070, Q10739, Q11005, Q18206, Q19204, Q20459, Q20942, Q20958, Q22396, Q22710, Q5RES1, Q5W7F4, Q61EX6, Q62381, Q7Z0M7, Q8JI28, Q8MPP3, Q93243, Q93542, Q94316

Diamond homologs: A0A0C5PRQ1, A0FKN6, A8Q2D1, C9D7R2, C9D7R3, D2KBH9, D5FM34, D5FM37, D5FM38, K7Z9Q9, O16977, O17264, O43897, O57382, O57460, O62243, P07584, P0DM61, P0DM62, P13497, P28825, P28826, P31579, P31580, P31581, P42674, P55112, P55113, P55114, P55115, P84748, P91137, P98060, P98061, P98063, P98068, P98069, P98070, Q16819, Q16820

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	134
Likely benign	18
Benign	37

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4074	NM_012464.5(TLL1):c.544A>C (p.Met182Leu)	Pathogenic
4076	NM_012464.5(TLL1):c.1885A>G (p.Ile629Val)	Pathogenic
4277527	NM_012464.5(TLL1):c.605A>G (p.Tyr202Cys)	Likely pathogenic

SpliceAI

5388 predictions. Top by Δscore:

Variant	Effect	Δscore
4:165874070:GCCG:G	donor_gain	1.0000
4:165874072:CGGT:C	donor_loss	1.0000
4:165874073:GGTA:G	donor_loss	1.0000
4:165874074:GTA:G	donor_loss	1.0000
4:165874075:T:G	donor_loss	1.0000
4:165989376:TTTA:T	acceptor_loss	1.0000
4:165989377:TTA:T	acceptor_loss	1.0000
4:165989378:TA:T	acceptor_loss	1.0000
4:165989379:A:AG	acceptor_gain	1.0000
4:165989380:G:GG	acceptor_gain	1.0000
4:165989380:GC:G	acceptor_gain	1.0000
4:165989380:GCT:G	acceptor_gain	1.0000
4:165989380:GCTGT:G	acceptor_gain	1.0000
4:165989487:CACAG:C	donor_loss	1.0000
4:165989488:ACAG:A	donor_loss	1.0000
4:165989489:CAGGT:C	donor_loss	1.0000
4:165989490:AGGTA:A	donor_loss	1.0000
4:165989491:GG:G	donor_loss	1.0000
4:165989492:G:GA	donor_loss	1.0000
4:165989493:T:G	donor_loss	1.0000
4:165992865:GA:G	donor_gain	1.0000
4:165992896:TTTA:T	donor_gain	1.0000
4:165992923:GTACA:G	donor_gain	1.0000
4:165992928:G:GG	donor_gain	1.0000
4:165994358:GAAT:G	acceptor_gain	1.0000
4:165994531:CTGG:C	donor_loss	1.0000
4:165994532:TGGT:T	donor_loss	1.0000
4:165994533:GGTAA:G	donor_loss	1.0000
4:165994534:G:C	donor_loss	1.0000
4:165994534:G:GG	donor_gain	1.0000

AlphaMissense

6723 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:165995099:T:A	W185R	1.000
4:165995099:T:C	W185R	1.000
4:165995101:G:C	W185C	1.000
4:165995101:G:T	W185C	1.000
4:165995174:T:C	C210R	1.000
4:165995175:G:A	C210Y	1.000
4:166003392:T:C	C212R	1.000
4:166003395:T:C	C213R	1.000
4:166003396:G:A	C213Y	1.000
4:166003397:C:G	C213W	1.000
4:166003452:T:A	C232S	1.000
4:166003452:T:C	C232R	1.000
4:166003453:G:A	C232Y	1.000
4:166003453:G:C	C232S	1.000
4:166003453:G:T	C232F	1.000
4:166003454:T:G	C232W	1.000
4:166003506:C:G	H250D	1.000
4:166003508:T:A	H250Q	1.000
4:166003508:T:G	H250Q	1.000
4:166003513:A:G	H252R	1.000
4:166007957:T:C	F276L	1.000
4:166007958:T:C	F276S	1.000
4:166007958:T:G	F276C	1.000
4:166007959:T:A	F276L	1.000
4:166007959:T:G	F276L	1.000
4:166008041:T:C	F304L	1.000
4:166008042:T:G	F304C	1.000
4:166008043:C:A	F304L	1.000
4:166008043:C:G	F304L	1.000
4:166025396:T:C	C375R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001840 (4:165912960 T>C), RS1000003645 (4:165971494 C>A), RS1000008071 (4:165917178 G>A), RS1000029028 (4:166070800 T>A,C), RS1000060563 (4:165990875 A>G), RS1000066076 (4:165997964 C>T), RS1000068585 (4:165911717 A>G), RS1000072379 (4:166017816 T>C), RS1000095863 (4:166103873 T>G), RS1000108418 (4:166078383 A>G), RS1000112104 (4:165959320 G>A), RS1000139766 (4:166078140 G>A,T), RS10001573 (4:166018683 G>A,T), RS1000159502 (4:165977421 C>T), RS1000162199 (4:165888239 A>G)

Disease associations

OMIM: gene MIM:606742 | disease phenotypes: MIM:613087

GenCC curated gene-disease

Disease	Classification	Inheritance
atrial septal defect 6	Strong	Autosomal dominant
mitral valve prolapse	Limited	Autosomal dominant
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (3): atrial septal defect 6 (MONDO:0013123), mitral valve prolapse (MONDO:0004910), congenital heart disease (MONDO:0005453)

Orphanet (1): Interatrial communication (Orphanet:1478)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000961	Cyanosis
HP:0001279	Syncope
HP:0001297	Stroke
HP:0001508	Failure to thrive
HP:0001631	Atrial septal defect
HP:0001633	Abnormal mitral valve morphology
HP:0001635	Congestive heart failure
HP:0001653	Mitral regurgitation
HP:0001662	Bradycardia
HP:0001678	Atrioventricular block
HP:0001694	Right-to-left shunt
HP:0001708	Right ventricular failure
HP:0001712	Left ventricular hypertrophy
HP:0001907	Thromboembolism
HP:0001962	Palpitations
HP:0002090	Pneumonia
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002205	Recurrent respiratory infections
HP:0002326	Transient ischemic attack
HP:0002718	Recurrent bacterial infections
HP:0002789	Tachypnea
HP:0002795	Abnormal respiratory system physiology
HP:0002875	Exertional dyspnea
HP:0003546	Exercise intolerance
HP:0003577	Congenital onset
HP:0004749	Atrial flutter
HP:0004755	Supraventricular tachycardia

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001762_475	Obesity-related traits	8.000000e-06
GCST001860_10	Multiple sclerosis	5.000000e-06
GCST002037_10	Post-traumatic stress disorder (asjusted for relatedness)	5.000000e-07
GCST002037_7	Post-traumatic stress disorder (asjusted for relatedness)	1.000000e-07
GCST002038_1	Post-traumatic stress disorder	3.000000e-09
GCST002038_2	Post-traumatic stress disorder	1.000000e-06
GCST002337_40	Amyotrophic lateral sclerosis (sporadic)	5.000000e-06
GCST003134_15	Cerebrospinal fluid clusterin levels	5.000000e-06
GCST003139_4	Glomerular filtration rate in chronic kidney disease	1.000000e-06
GCST004160_1	Hepatocellular carcinoma in post hepatitis C eradication by interferon therapy	3.000000e-08
GCST004640_20	Western dietary pattern	8.000000e-06
GCST005214_4	Bone mineral density change response to combined chemotherapy in acute lymphoblastic leukemia	8.000000e-06
GCST005606_3	Response to hepatitis B vaccine	6.000000e-06
GCST006412_43	Intraocular pressure	5.000000e-08
GCST007018_7	Serum bilirubin levels in metabolic syndrome	3.000000e-06
GCST008152_86	Weight	3.000000e-06
GCST008156_108	Hip circumference adjusted for BMI	2.000000e-06
GCST008158_141	Body mass index	7.000000e-06
GCST008159_67	Waist-to-hip ratio adjusted for BMI	5.000000e-06
GCST009723_86	Vertical cup-disc ratio (adjusted for vertical disc diameter)	3.000000e-07
GCST009724_39	Vertical cup-disc ratio (multi-trait analysis)	3.000000e-09
GCST010002_19	Refractive error	8.000000e-11
GCST011773_28	Type 1 diabetes (age at diagnosis)	5.000000e-06
GCST012230_2	Waist-to-hip ratio adjusted for BMI	4.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0005112	gestational age
EFO:0007859	response to interferon
EFO:0008111	diet measurement
EFO:0007965	response to combination chemotherapy
EFO:0004645	response to vaccine
EFO:0004695	intraocular pressure measurement
EFO:0004570	bilirubin measurement
EFO:0004338	body weight
EFO:0008039	BMI-adjusted hip circumference
EFO:0004340	body mass index
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0006939	cup-to-disc ratio measurement
EFO:0004918	age at diagnosis

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008945	Mitral Valve Prolapse	C14.280.484.400.500
C567764	Atrial Septal Defect 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295664 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.51	Ki	0.031	nM	CHEMBL4212386
9.62	Ki	0.24	nM	CHEMBL4214046
7.00	IC50	100	nM	CHEMBL4207308

PubChem BioAssay actives

3 with measured affinity, of 3 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[2-ethoxy-4-[5-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methylcarbamoyl]furan-2-yl]benzoyl]amino]butanedioic acid	1385213: Binding affinity to TLL1 (unknown origin) using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2 as substrate incubated for 3.5 hrs followed by substrate addition by FRET assay	ki	<0.0001	uM
[3-ethoxy-5-[5-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methylcarbamoyl]furan-2-yl]phenyl]phosphonic acid	1385213: Binding affinity to TLL1 (unknown origin) using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2 as substrate incubated for 3.5 hrs followed by substrate addition by FRET assay	ki	0.0002	uM
N-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methyl]-5-phenylfuran-2-carboxamide	1385191: Inhibition of recombinant human full length TLL1 using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2) as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins	ic50	0.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, decreases expression	3
Benzo(a)pyrene	decreases methylation, decreases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
potassium chromate(VI)	decreases expression	1
triadimefon	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
bisphenol S	decreases expression, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Arbutin	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Vanadates	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Zinc Sulfate	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4199881	Binding	Inhibition of recombinant human full length TLL1 using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2) as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins	Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT05631730	PHASE3	RECRUITING	Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function