TGM1

Summary

TGM1 (transglutaminase 1, HGNC:11777) is a protein-coding gene on chromosome 14q12, encoding Protein-glutamine gamma-glutamyltransferase K (P22735). Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3’ UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE).

Source: NCBI Gene 7051 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 1 (Definitive, GenCC) — +5 more curated relationships
• Clinical variants (ClinVar): 1,191 total — 123 pathogenic, 117 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000359

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11777
Approved symbol	TGM1
Name	transglutaminase 1
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	TGASE, TGK, LI, LI1
Ensembl gene	ENSG00000092295
Ensembl biotype	protein_coding
OMIM	190195
Entrez	7051

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000206765, ENST00000544573, ENST00000558074, ENST00000559136, ENST00000559669, ENST00000560226, ENST00000560443, ENST00000560478, ENST00000561067, ENST00000879556

RefSeq mRNA: 1 — MANE Select: NM_000359 NM_000359

CCDS: CCDS9622

Canonical transcript exons

ENST00000206765 — 15 exons

Exon	Start	End
ENSE00000654393	24254972	24255253
ENSE00000654394	24255364	24255517
ENSE00000654395	24255989	24256077
ENSE00000654398	24258535	24258673
ENSE00000654401	24259940	24260058
ENSE00000654402	24260450	24260698
ENSE00000654403	24261695	24261883
ENSE00000889427	24249114	24249541
ENSE00000889428	24254152	24254288
ENSE00000889429	24254664	24254824
ENSE00000889430	24259075	24259249
ENSE00000889431	24262034	24262354
ENSE00002538940	24263089	24263177
ENSE00003571512	24258285	24258388
ENSE00003672463	24259704	24259811

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2084 / max 275.5406, expressed in 199 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142572	1.6284	129
142574	0.2419	96
142573	0.1005	37
142575	0.0923	62
142577	0.0578	29
142576	0.0368	12
142571	0.0343	10
142569	0.0138	5
142570	0.0024	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.64	gold quality
esophagus mucosa	UBERON:0002469	98.98	gold quality
skin of leg	UBERON:0001511	94.78	gold quality
skin of abdomen	UBERON:0001416	94.74	gold quality
zone of skin	UBERON:0000014	94.71	gold quality
vagina	UBERON:0000996	89.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.63	gold quality
cerebellar hemisphere	UBERON:0002245	87.93	gold quality
cerebellar cortex	UBERON:0002129	87.79	gold quality
cerebellum	UBERON:0002037	87.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.49	gold quality
esophagus	UBERON:0001043	84.34	gold quality
tonsil	UBERON:0002372	83.96	gold quality
minor salivary gland	UBERON:0001830	82.78	gold quality
omental fat pad	UBERON:0010414	81.94	gold quality
saliva-secreting gland	UBERON:0001044	81.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.75	gold quality
ectocervix	UBERON:0012249	79.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.89	gold quality
tibial nerve	UBERON:0001323	78.56	gold quality
upper lobe of left lung	UBERON:0008952	78.13	gold quality
uterine cervix	UBERON:0000002	76.45	gold quality
fallopian tube	UBERON:0003889	76.02	gold quality
granulocyte	CL:0000094	74.88	gold quality
lung	UBERON:0002048	74.57	gold quality
right uterine tube	UBERON:0001302	74.26	gold quality
sural nerve	UBERON:0015488	73.90	gold quality
right frontal lobe	UBERON:0002810	73.33	gold quality
adipose tissue	UBERON:0001013	72.91	gold quality
left uterine tube	UBERON:0001303	72.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, E2F1, HOXA7, JUN, NR3C1, SMAD7, SP1, TP53

miRNA regulators (miRDB)

12 targeting TGM1, 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-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-6779-3P	97.51	65.82	789
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-549A-5P	96.35	68.08	587
HSA-MIR-4497	92.25	64.06	134

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• proposed that tTGase-mediated cross-linking is an another form of core histone modification and it may play a role of chromatin condensation during erythrocyte differentiation (PMID:12054678)
• This enzyme is expressed in vivo in normal lung, preinvasive bronchial lesions, and lung cancer. (PMID:12654631)
• transglutaminase 1 has a role in keratinocyte terminal differentiation after activation by TIG3 (PMID:12928434)
• LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in Netherton syndrome (PMID:15304086)
• Treatment of human umbilical vein endothelial cells (HUVEC) with atorvastatin (1-10 microM) caused a clear increased expression of tTgase in both permeabilised and non-permeabilised HUVEC. (PMID:15313180)
• analysis of transglutaminase 1 mutations in autosomal recessive congenital ichthyosis in Egyptian families (PMID:15665393)
• In HEK 293T cell culture, transglutaminase 1 cross-links the N-terminal fragments of mutant huntingtin protein, therefore it could be involved in the cross-linking of huntingtin into intranuclear inclusions in Huntington disease. (PMID:15715085)
• Beta ig-h3 induces keratinocyte differentiation via modulation of involucrin and transglutaminase expression through the integrin alpha3beta1 and the phosphatidylinositol 3-kinase/Akt signaling pathway (PMID:15805105)
• a non-invasive assessment of scale, nail and hair could be of diagnostic utility in distinguishing patients across a full range of phenotypes with deficiency in TGM1-encoded enzymeactivity from other causes of autosomal recessive ichthyosis. (PMID:16133457)
• Vitamin E treatment also led to increased expression of a known PPARgamma target gene involved in terminal keratinocytes differentiation, the transglutaminase-1. (PMID:16530159)
• Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase (PMID:16604191)
• a three-dimensional model of the human transglutaminase 1 provides insights into the understanding of lamellar ichthyosis (PMID:17024410)
• occurrence of an unusual TG 3’ splice site in intron 6 (PMID:17672918)
• intestinal damage is associated with the production of anti-tTG IgA and anti-TGe IgA in dermatitis herpetiformis patients (PMID:17762854)
• Transglutaminase induces protofibril-like amyloid beta-protein assemblies that are protease-resistant and inhibit long-term potentiation (PMID:18397883)
• Transglutaminases demonstrate cross-linking activity in Alzheimer lesions, suggesting TG1 and TG2 are involved in protein aggregation processes underlying formation of senile plaques, amyloid angiopathy and/or neurofibrillary tangles in Alzhemier disease. (PMID:18673368)
• transglutaminase-1 mutation spectrum and confirms that despite genetic and phenotypic heterogeneity in Autosomal recessive congenital ichthyosis (PMID:18948357)
• The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis. (PMID:19197536)
• Study expands the TGM1 mutation spectrum and summarizes the current knowledge of TGM1 mutations. (PMID:19241467)
• role for cell surface tTG in the regulation of the joint PDGFR/integrin signaling and PDGFR-dependent cell responses (PMID:19386600)
• TG1-catalyzed cross-linking and consequent polymerization of cytoskeletal and cytoskeleton-associated proteins may underlie corpora amylacea formation. (PMID:19464759)
• four novel mutations in TGM1 gene result in decrease or absence of TGase activity in the skin and, as a consequence, cause the phenotype of autosomal recessive lamellar ichthyosis (PMID:19486042)
• epidermal transglutaminase may have autoantibodies in dermatitis herpetiformis and celiac disease (PMID:19516268)
• Case Report: Autosomal recessive congenital ichthyosis and congenital hypothyroidism in a Tunisian patient with a nonsense mutation in TGM1. (PMID:19556108)
• A specific colorimetric assay for measuring transglutaminase 1 activity is reported. (PMID:19646949)
• Mutations are closely related to previously described ones in bathing suit ichthyosis and self-healing collodion baby variants of lamellar ichthyosis and clustered in exons 5, 6 and 7 of TMG1 (PMID:19863506)
• ALOX12B mutations are the leading cause of self-improving collodion ichthyosis in Scandinavia, followed by ALOXE3 mutations, and TGM1 mutations (PMID:19890349)
• findings identify tissue transglutaminase as a key participant in an EGFR/Src-signaling pathway in breast-cancer cells and a potential target for inhibiting EGFR-promoted tumor progression. (PMID:20080707)
• Transglutaminase1 and its preferred substrate peptide K5 have a role in lamellar ichthyosis (PMID:20167857)
• misfolding of TG1 mutants leads to ubiquitinylation and accumulation in the ER and aggresomes, and that abnormal intracellular processing of TG1 mutants may be an underlying cause of ichthyosis. (PMID:20663883)
• These data indicate that loss of E2F7 during the initiation of differentiation leads to the derepression of Sp1 and subsequent transcription of differentiation-specific genes such as epidermal type I transglutaminase. (PMID:21248772)
• beta-actin is a target for the activity of recombinant human transglutaminase 1 in cultured chick telecephalon cell cultures. (PMID:21789544)
• We conclude that TG1-catalysed cross-linking, regulated by TIG3, might play an important role in the formation of neuronal tau inclusions in certain tauopathies (PMID:22009441)
• TG1 and TG2 isoenzymes are highly active with the major activity attributed to TG1 in human saliva. (PMID:22080209)
• Transglutaminase in epidermis and neurological disease. (PMID:22220473)
• TGM1 genotypes of the family were used to determine parental origins of the mutations. (PMID:22311480)
• Our splicing assay, together with bioinformatic prediction tools, supports the pathological effect of the recently identified c.984+1G>A mutation in the TGM1 gene and unravels the molecular mechanism by which c.984+1G>A acts. (PMID:22435431)
• Two mutations of the TGM1 gene,c.2278C>T and c.1223_1227delACACA which are observed in high frequency in Galician patients with autosomal recessive congenital ichthyosis, were most likely founded in the Galician territory instead of being brought here by migrants. (PMID:22511925)
• Autosomal recessive congenital ichthyosis patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. (PMID:22622417)
• These findings confirm the hypothesis that only a restricted spectrum of TGM1 mutations leads to a bathing suit ichthyosis and/or a self-improving collodion ichthyosis phenotype. (PMID:22801880)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgm1l3	ENSDARG00000005913
danio_rerio	tgm1	ENSDARG00000017799
danio_rerio	tgm1l4	ENSDARG00000101407
danio_rerio	tgm1l2	ENSDARG00000101595
danio_rerio	tgm1l1	ENSDARG00000102106
mus_musculus	Tgm1	ENSMUSG00000022218
rattus_norvegicus	Tgm1	ENSRNOG00000020136
drosophila_melanogaster	Tg	FBGN0031975

Paralogs (8): TGM5 (ENSG00000104055), F13A1 (ENSG00000124491), TGM3 (ENSG00000125780), TGM7 (ENSG00000159495), TGM4 (ENSG00000163810), EPB42 (ENSG00000166947), TGM6 (ENSG00000166948), TGM2 (ENSG00000198959)

Protein

Protein identifiers

Protein-glutamine gamma-glutamyltransferase K — P22735 (reviewed: P22735)

Alternative names: Epidermal TGase, Transglutaminase K, Transglutaminase-1

All UniProt accessions (8): P22735, A0A0G2JL93, H0YKI6, H0YLJ6, H0YLT9, H0YMQ8, H0YN27, H0YNM4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross-linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation.

Subcellular location. Cell membrane. Cytoplasm. Cytosol.

Post-translational modifications. The membrane anchorage region possesses a cluster of five cysteines within which fatty acid(s) may become thioester-linked. It is subject to phorbol ester-stimulated phosphorylation and is hypersensitive to proteolysis, which releases the enzyme in a soluble form. Tyrosine-phosphorylated. The N-terminus is blocked. Activated by proteolytic processing. Myristoylated. Palmitoylated.

Disease relevance. Ichthyosis, congenital, autosomal recessive 1 (ARCI1) [MIM:242300] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Ca(2+) ion per subunit.

Similarity. Belongs to the transglutaminase superfamily. Transglutaminase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22735-1	1	yes
P22735-2	2

RefSeq proteins (1): NP_000350* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001102	Transglutaminase_N	Domain
IPR002931	Transglutaminase-like	Domain
IPR008958	Transglutaminase_C	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013808	Transglutaminase_AS	Active_site
IPR014756	Ig_E-set	Homologous_superfamily
IPR023608	Transglutaminase_animal	Family
IPR036238	Transglutaminase_C_sf	Homologous_superfamily
IPR036985	Transglutaminase-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050779	Transglutaminase	Family

Pfam: PF00868, PF00927, PF01841

Enzyme classification (BRENDA):

• EC 2.3.2.13 — protein-glutamine gamma-glutamyltransferase (BRENDA: 68 organisms, 476 substrates, 772 inhibitors, 122 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

60 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PUTRESCINE	0.035–9.63	13
L-LYSINE	2.9–15.8	6
N-CBZ-GLN-GLY	12.83–59.5	5
HYDROXYLAMINE	1.37–61.9	4
NALPHA-BENZYLOXYCARBONYL-L-GLN-GLY	11.2–30	4
CASEIN	0.006–0.012	3
CBZ-GLN-GLY	0.0169–5.9	3
CBZ-GLN-GLY-OH	3.53–8.55	3
METHYLAMINE	0.024–0.061	3
MONODANSYLCADAVERINE	0.01–0.034	3
N-CARBOXYBENZOYL-L-GLUTAMINYL-GLYCINE	0.0547–69.4	3
PENTYLAMINE	0.0029–0.0203	3
Z-GLN-GLY	1.8–11.6	3
ACETYL-ALPHAS1-CASEIN	0.0029–0.0032	2
GTP	0.0044–0.01	2

Catalyzed reactions (Rhea), 1 shown:

• L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+) (RHEA:54816)

UniProt features (120 total): sequence variant 71, binding site 10, strand 8, modified residue 7, sequence conflict 6, region of interest 4, chain 3, active site 3, site 2, compositionally biased region 2, mutagenesis site 1, turn 1, helix 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2XZZ	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22735-F1	85.04	0.74

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 (5): 436; 459; 93–94 (cleavage (activation)); 573–574 (cleavage (activation)); 377

Ligand- & substrate-binding residues (10): 327; 330; 333; 335; 406; 408; 430; 499; 548; 553

Post-translational modifications (7): 22, 24, 68, 82, 85, 92, 95

Mutagenesis-validated functional residues (1):

Position	Phenotype
377	catalytically inactive. does not localize to plasma membrane, accumulates in the endoplasmic reticulum.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 239 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_KERATINOCYTE_PROLIFERATION, GCANCTGNY_MYOD_Q6, GOBP_PEPTIDE_CROSS_LINKING, SHEPARD_BMYB_MORPHOLINO_DN, chr14q12, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, TCF4_Q5, GOBP_REGULATION_OF_KERATINOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELL_CYCLE, MODULE_99, TGANTCA_AP1_C, TGACATY_UNKNOWN, MYOD_Q6, GOBP_EPIDERMIS_DEVELOPMENT

GO Biological Process (9): positive regulation of keratinocyte proliferation (GO:0010838), keratinocyte differentiation (GO:0030216), protein modification process (GO:0036211), cell envelope organization (GO:0043163), positive regulation of cell cycle (GO:0045787), cornification (GO:0070268), peptide cross-linking (GO:0018149), keratinization (GO:0031424), animal organ development (GO:0048513)

GO Molecular Function (6): protein-glutamine gamma-glutamyltransferase activity (GO:0003810), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (5): cornified envelope (GO:0001533), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
epidermal cell differentiation	1
skin development	1
protein metabolic process	1
macromolecule modification	1
external encapsulating structure organization	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
programmed cell death	1
keratinization	1
cornified envelope assembly	1
protein modification process	1
keratinocyte differentiation	1
multicellular organismal process	1
anatomical structure development	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
protein binding	1
cation binding	1
binding	1
catalytic activity	1
transferase activity	1
plasma membrane	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

1470 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGM1	NIPAL4	Q0D2K0	958
TGM1	ABCA12	Q86UK0	951
TGM1	CYP4F22	Q6NT55	916
TGM1	IVL	P07476	896
TGM1	ALOXE3	Q9BYJ1	872
TGM1	ALOX12B	O75342	871
TGM1	SPRR1B	P22528	869
TGM1	LORICRIN	P23490	867
TGM1	FLG2	Q5D862	810
TGM1	FLG	P20930	808
TGM1	CSTA	P01040	779
TGM1	GRHL3	Q8TE85	766
TGM1	PNPLA1	Q8N8W4	764
TGM1	RABGGTA	Q92696	726
TGM1	KRT10	P13645	720

IntAct

246 interactions, top by confidence:

A	B	Type	Score
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
TGM1	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.560
TGM1	LCE3A	psi-mi:“MI:0915”(physical association)	0.560
TGM1	LCE4A	psi-mi:“MI:0915”(physical association)	0.560
TGM1	LCE1E	psi-mi:“MI:0915”(physical association)	0.560
ALPP	TGM1	psi-mi:“MI:0915”(physical association)	0.560
ITGB4	TGM1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
TGM1	VSTM4	psi-mi:“MI:0915”(physical association)	0.560
TACC2	TGM1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	SULT4A1	psi-mi:“MI:0915”(physical association)	0.560
SCARF1	TGM1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	NUBP2	psi-mi:“MI:0915”(physical association)	0.560
TGM1	LCE1B	psi-mi:“MI:0915”(physical association)	0.560
TGM1	C1QTNF1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	TRAPPC14	psi-mi:“MI:0915”(physical association)	0.560
TGM1	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
GSTP1	TGM1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	MYPOP	psi-mi:“MI:0915”(physical association)	0.560
TGM1	VASN	psi-mi:“MI:0915”(physical association)	0.560
CXCL16	TGM1	psi-mi:“MI:0915”(physical association)	0.560
IFI30	TGM1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	NECTIN2	psi-mi:“MI:0915”(physical association)	0.560
TGM1	JOSD1	psi-mi:“MI:0915”(physical association)	0.560
TGM1	ACADL	psi-mi:“MI:0915”(physical association)	0.560
TGM1	TGM1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (262): TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), TGM1 (Two-hybrid), TGM1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0Q3IBS1, I1H0V9, O08619, O18733, O54732, O82088, O88917, O94910, O97831, P00488, P08587, P13696, P14780, P22735, P22758, P23606, P30086, P31044, P41245, P41246, P51176, P51511, P52176, P52181, P52183, P54185, P93003, Q3YIX4, Q41261, Q5R4R0, Q656A5, Q80TR1, Q8MK67, Q8VIN1, Q8VWH2, Q93WI9, Q95220, Q9ASJ1, Q9D9G2, Q9FIT4

Diamond homologs: A6QP57, D4A5U3, O08619, O43548, O46510, O95932, P00488, P08587, P16452, P21980, P21981, P22735, P22758, P23606, P49221, P51176, P52181, P52183, Q01841, Q05187, Q08188, Q08189, Q8BH61, Q8BZH1, Q96PF1, Q99041, Q9D7I9, Q9GLK0, Q9JLF6, Q9WVJ6, P49222, P12260

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HOXA7	“down-regulates quantity by repression”	TGM1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1191 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	123
Likely pathogenic	117
Uncertain significance	249
Likely benign	529
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1050812	NM_000359.3(TGM1):c.674_675delinsCT (p.Arg225Pro)	Pathogenic
1074310	NM_000359.3(TGM1):c.211C>T (p.Arg71Ter)	Pathogenic
1195231	NM_000359.3(TGM1):c.1264A>T (p.Lys422Ter)	Pathogenic
12478	NM_000359.3(TGM1):c.1297del (p.Trp433fs)	Pathogenic
12482	NM_000359.3(TGM1):c.479C>G (p.Ser160Cys)	Pathogenic
12486	NM_000359.3(TGM1):c.1135G>C (p.Val379Leu)	Pathogenic
12490	NM_000359.3(TGM1):c.2114del (p.Gln705fs)	Pathogenic
12493	NM_000359.3(TGM1):c.1175G>A (p.Gly392Asp)	Pathogenic
12498	NM_000359.3(TGM1):c.866A>C (p.Asn289Thr)	Pathogenic
127067	NM_000359.3(TGM1):c.1621A>C (p.Thr541Pro)	Pathogenic
1360806	NM_000359.3(TGM1):c.2226-2_2226-1dup	Pathogenic
1378703	NM_000359.3(TGM1):c.455del (p.Leu152fs)	Pathogenic
1392347	NM_000359.3(TGM1):c.1750G>T (p.Glu584Ter)	Pathogenic
1396708	NM_000359.3(TGM1):c.739_740del (p.Phe247fs)	Pathogenic
1407149	NM_000359.3(TGM1):c.614del (p.Leu205fs)	Pathogenic
1413628	NM_000359.3(TGM1):c.430G>C (p.Gly144Arg)	Pathogenic
1416950	NM_000359.3(TGM1):c.799dup (p.Tyr267fs)	Pathogenic
1419049	NM_000359.3(TGM1):c.607C>T (p.Gln203Ter)	Pathogenic
1428647	NM_000359.3(TGM1):c.890del (p.Val297fs)	Pathogenic
1429740	NM_000359.3(TGM1):c.1335_1344del (p.Arg445fs)	Pathogenic
1435036	NM_000359.3(TGM1):c.1552del (p.Val518fs)	Pathogenic
1452303	NM_000359.3(TGM1):c.196_197insGT (p.Ser66fs)	Pathogenic
1453684	NM_000359.3(TGM1):c.327del (p.Met109fs)	Pathogenic
1454166	NM_000359.3(TGM1):c.1956C>A (p.Tyr652Ter)	Pathogenic
1456148	NM_000359.3(TGM1):c.877-2A>C	Pathogenic
1456402	NM_000359.3(TGM1):c.1947_1948dup (p.Val650fs)	Pathogenic
1458607	NM_000359.3(TGM1):c.408_411dup (p.Glu138fs)	Pathogenic
1458904	NM_000359.3(TGM1):c.932dup (p.Tyr312fs)	Pathogenic
1459722	NM_000359.3(TGM1):c.2090T>G (p.Leu697Ter)	Pathogenic
1917950	NM_000359.3(TGM1):c.1802del (p.Ile601fs)	Pathogenic

SpliceAI

2238 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24254150:A:AC	donor_gain	1.0000
14:24254150:AC:A	donor_gain	1.0000
14:24254151:C:CC	donor_gain	1.0000
14:24254151:CC:C	donor_gain	1.0000
14:24254151:CCCAA:C	donor_gain	1.0000
14:24254285:GTAA:G	acceptor_gain	1.0000
14:24254286:TAA:T	acceptor_gain	1.0000
14:24254289:C:CC	acceptor_gain	1.0000
14:24254290:T:G	acceptor_loss	1.0000
14:24254659:TTCAC:T	donor_loss	1.0000
14:24254660:TCAC:T	donor_loss	1.0000
14:24254661:CACCG:C	donor_loss	1.0000
14:24254662:A:AC	donor_gain	1.0000
14:24254662:A:C	donor_loss	1.0000
14:24254663:C:CC	donor_gain	1.0000
14:24254720:G:A	donor_gain	1.0000
14:24254728:T:A	donor_gain	1.0000
14:24254820:GTCCG:G	acceptor_gain	1.0000
14:24254821:TCCG:T	acceptor_gain	1.0000
14:24254822:CCG:C	acceptor_gain	1.0000
14:24254822:CCGC:C	acceptor_gain	1.0000
14:24254823:CG:C	acceptor_gain	1.0000
14:24254823:CGC:C	acceptor_gain	1.0000
14:24254824:GCTG:G	acceptor_loss	1.0000
14:24254825:C:CC	acceptor_gain	1.0000
14:24254965:CACTT:C	donor_loss	1.0000
14:24254966:ACTTA:A	donor_loss	1.0000
14:24254967:CTTAC:C	donor_loss	1.0000
14:24254968:TTA:T	donor_loss	1.0000
14:24254969:TA:T	donor_loss	1.0000

AlphaMissense

5318 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24256001:G:C	F493L	1.000
14:24256001:G:T	F493L	1.000
14:24256003:A:G	F493L	1.000
14:24258298:T:A	Q463H	1.000
14:24258298:T:G	Q463H	1.000
14:24258302:G:T	P462H	1.000
14:24258375:A:G	W438R	1.000
14:24258375:A:T	W438R	1.000
14:24258379:A:C	H436Q	1.000
14:24258379:A:T	H436Q	1.000
14:24258381:G:C	H436D	1.000
14:24258381:G:T	H436N	1.000
14:24258382:G:C	F435L	1.000
14:24258382:G:T	F435L	1.000
14:24258384:A:G	F435L	1.000
14:24258388:C:A	W433C	1.000
14:24258388:C:G	W433C	1.000
14:24258536:A:G	W433R	1.000
14:24258536:A:T	W433R	1.000
14:24258544:T:A	D430V	1.000
14:24258620:G:C	H405D	1.000
14:24258622:G:T	A404D	1.000
14:24259102:A:G	W378R	1.000
14:24259102:A:T	W378R	1.000
14:24259110:C:T	G375D	1.000
14:24259160:G:C	S358R	1.000
14:24259160:G:T	S358R	1.000
14:24259162:T:G	S358R	1.000
14:24259208:C:A	W342C	1.000
14:24259208:C:G	W342C	1.000

dbSNP variants (sampled 300 via entrez): RS1000050155 (14:24261750 G>A,C), RS1000189283 (14:24258623 C>A,T), RS1000412552 (14:24252411 G>C,T), RS1000514262 (14:24256954 A>T), RS1000651652 (14:24256784 A>C), RS1000703779 (14:24251414 G>A), RS1000761015 (14:24257276 C>T), RS1000967454 (14:24250053 A>G), RS1001320918 (14:24253904 C>G,T), RS1001592306 (14:24250482 C>A,T), RS1001592485 (14:24259883 C>G,T), RS1001720420 (14:24264625 T>C,G), RS1001843940 (14:24260785 T>A,C), RS1002867973 (14:24251063 A>G), RS1003728593 (14:24257728 A>G)

Disease associations

OMIM: gene MIM:190195 | disease phenotypes: MIM:242300, MIM:615022, MIM:127550, MIM:154500, MIM:268130, MIM:613990

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 1	Definitive	Autosomal recessive
bathing suit ichthyosis	Supportive	Autosomal recessive
self-healing collodion baby	Supportive	Autosomal recessive
acral self-healing collodion baby	Supportive	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Supportive	Autosomal recessive

Mondo (14): autosomal recessive congenital ichthyosis 1 (MONDO:0009441), lamellar ichthyosis (MONDO:0017778), autosomal recessive congenital ichthyosis 7 (MONDO:0014009), ichthyosis (MONDO:0019269), dyskeratosis congenita (MONDO:0015780), autosomal recessive congenital ichthyosis (MONDO:0017265), Treacher Collins syndrome 1 (MONDO:0007944), dyskeratosis congenita, autosomal dominant 1 (MONDO:0007485), Revesz syndrome (MONDO:0009990), dyskeratosis congenita, autosomal dominant 3 (MONDO:0013522), bathing suit ichthyosis (MONDO:0015085), self-healing collodion baby (MONDO:0017267), acral self-healing collodion baby (MONDO:0017268), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306)

Orphanet (7): Lamellar ichthyosis (Orphanet:313), Congenital ichthyosiform erythroderma (Orphanet:79394), Ichthyosis (Orphanet:79354), Dyskeratosis congenita (Orphanet:1775), Autosomal recessive congenital ichthyosis (Orphanet:281097), Treacher-Collins syndrome (Orphanet:861), Revesz syndrome (Orphanet:3088)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001072	Thickened skin
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001944	Dehydration
HP:0002164	Nail dysplasia
HP:0002205	Recurrent respiratory infections
HP:0002828	Multiple joint contractures
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007431	Congenital ichthyosiform erythroderma
HP:0007460	Autoamputation of digits

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
D017490	Ichthyosis, Lamellar	C16.131.831.512.400.410; C16.320.850.400.410; C16.614.492.400.410; C17.800.428.333.250.410; C17.800.804.512.400.410; C17.800.827.400.410
C565079	Dyskeratosis Congenita, Autosomal Dominant (supp.)
C538371	Revesz Debuse syndrome (supp.)
C565473	Self-Healing Collodion Baby (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2810 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

5 measured of 17 human assays (17 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]-2-bromo-acetamide (6e)	IC50	3.9 nM
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]prop-2-enamide (3e)	IC50	125 nM
[2-[[2-[4-(1-Adamantylmethoxycarbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxoethyl]-dimethyl-sulfonium bromide (1f)	IC50	775 nM
[2-[[2-[4-(Adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxo-ethyl]-dimethyl-sulfonium bromide (1e)	IC50	889 nM
1-Adamantylmethyl 4-[2-(prop-2-enoylamino)acetyl]piperazine-1-carboxylate (3f)	IC50	1620 nM

ChEMBL bioactivities

62 potent at pChembl≥5 of 83 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	IC50	18	nM	CHEMBL2086889
6.60	IC50	250	nM	CHEMBL3092842
6.60	IC50	250	nM	CHEMBL193220
6.04	IC50	910	nM	CHEMBL2152090
6.02	IC50	950	nM	CHEMBL2086891
5.92	IC50	1200	nM	CHEMBL2152204
5.85	IC50	1400	nM	CHEMBL2086505
5.77	IC50	1700	nM	CHEMBL2086530
5.75	IC50	1800	nM	CHEMBL2089397
5.75	IC50	1800	nM	CHEMBL2086542
5.62	IC50	2400	nM	CHEMBL2086890
5.60	IC50	2500	nM	CHEMBL2086519
5.58	IC50	2600	nM	CHEMBL2086524
5.57	IC50	2700	nM	CHEMBL2089399
5.54	IC50	2900	nM	CHEMBL2089391
5.54	IC50	2900	nM	CHEMBL2089396
5.52	IC50	3000	nM	CHEMBL2086544
5.51	IC50	3100	nM	CHEMBL2367730
5.47	IC50	3400	nM	CHEMBL2086528
5.47	IC50	3400	nM	CHEMBL2086540
5.44	IC50	3600	nM	CHEMBL2089389
5.43	IC50	3700	nM	CHEMBL2089388
5.42	IC50	3800	nM	CHEMBL2086538
5.39	IC50	4100	nM	CHEMBL2086479
5.39	IC50	4100	nM	CHEMBL2086507
5.39	IC50	4100	nM	CHEMBL2086525
5.38	IC50	4200	nM	CHEMBL2086531
5.35	IC50	4500	nM	CHEMBL2086529
5.34	IC50	4600	nM	CHEMBL2089398
5.34	IC50	4600	nM	CHEMBL2089400
5.31	IC50	4900	nM	CHEMBL2089386
5.30	IC50	5000	nM	CHEMBL2086518
5.29	IC50	5100	nM	CHEMBL2086512
5.29	IC50	5100	nM	CHEMBL2086543
5.27	IC50	5400	nM	CHEMBL2086526
5.27	IC50	5400	nM	CHEMBL2086527
5.25	IC50	5600	nM	CHEMBL2086480
5.25	IC50	5600	nM	CHEMBL2086541
5.23	IC50	5900	nM	CHEMBL2086532
5.22	IC50	6000	nM	CHEMBL2086522
5.21	IC50	6100	nM	CHEMBL2086509
5.21	IC50	6100	nM	CHEMBL2086534
5.21	IC50	6200	nM	CHEMBL190022
5.19	IC50	6400	nM	CHEMBL2086499
5.19	IC50	6500	nM	CHEMBL2086504
5.19	IC50	6400	nM	CHEMBL2086539
5.17	IC50	6700	nM	CHEMBL2086506
5.17	IC50	6800	nM	CHEMBL2086513
5.16	IC50	6900	nM	CHEMBL2086517
5.14	IC50	7200	nM	CHEMBL2086523

PubChem BioAssay actives

66 with measured affinity, of 181 total; 50 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
1-ethyl-3-(4-methoxyphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	0.0180	uM
1-[(5-methyl-[1,3]thiazolo[2,3-b][1,3,4]thiadiazol-4-ium-2-yl)sulfanyl]propan-2-one perchlorate	240715: Inhibitory concentration against guinea pig liver transglutaminase	ic50	0.2500	uM
methyl (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(E,2S)-6-methylsulfonyl-2-(phenylmethoxycarbonylamino)hex-5-enoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoate	1059554: Inhibition of human TGase1	ic50	0.2500	uM
benzyl N-[4-[4-(prop-2-enoylamino)piperidin-1-yl]sulfonylphenyl]carbamate	692646: Inhibition of human TGM1	ic50	0.9100	uM
tert-butyl 4-[2-chloro-4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	0.9500	uM
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxoethyl]-2-bromoacetamide	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	1.0000	uM
N-[2-(4-methoxyphenyl)ethyl]-4-[4-(prop-2-enoylamino)piperidin-1-yl]sulfonylbenzamide	692646: Inhibition of human TGM1	ic50	1.2000	uM
benzyl 4-[4-(prop-2-enoylamino)-2-(trifluoromethyl)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	1.4000	uM
N-[4-[4-(3-methyl-2-pyridinyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	1.7000	uM
benzyl 4-[[[4-(prop-2-enoylamino)phenyl]sulfonylamino]methyl]piperidine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	1.8000	uM
tert-butyl 4-[2-(prop-2-enoylamino)pyrimidin-5-yl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	1.8000	uM
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxoethyl]prop-2-enamide	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	2.2000	uM
tert-butyl 4-[2-fluoro-4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.4000	uM
cyclopentyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.5000	uM
N-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.6000	uM
benzyl 4-[[4-(prop-2-enoylamino)phenyl]sulfonylamino]piperidine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.7000	uM
benzyl N-[[1-[4-(prop-2-enoylamino)phenyl]sulfonylpiperidin-4-yl]methyl]carbamate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.9000	uM
benzyl (3S)-3-[[4-(prop-2-enoylamino)phenyl]sulfonylamino]pyrrolidine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	2.9000	uM
N-[5-[4-(adamantane-1-carbonyl)piperazin-1-yl]sulfonylpyrimidin-2-yl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.0000	uM
2-(1-adamantyl)ethyl 4-[2-[(2-bromoacetyl)amino]acetyl]piperazine-1-carboxylate	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	3.0000	uM
N-[4-[4-[(1S,2S)-2-phenylcyclopropanecarbonyl]piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.1000	uM
N-[4-[4-(adamantane-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.4000	uM
N-[5-[4-(cyclopropanecarbonyl)piperazin-1-yl]sulfonyl-2-pyridinyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.4000	uM
benzyl (3R)-3-[[4-(prop-2-enoylamino)phenyl]sulfonylamino]pyrrolidine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.6000	uM
benzyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.7000	uM
tert-butyl 4-[[6-(prop-2-enoylamino)-3-pyridinyl]sulfonyl]piperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	3.8000	uM
N-[4-[4-(piperidine-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.1000	uM
benzyl 4-[3-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.1000	uM
(4-fluorophenyl)methyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.1000	uM
N-[4-[4-(6-methyl-2-pyridinyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.2000	uM
N-[4-(4-pyridin-2-ylpiperazin-1-yl)sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.5000	uM
benzyl 4-[4-(prop-2-enoylamino)phenyl]sulfonyl-1,4-diazepane-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.6000	uM
benzyl N-[1-[4-(prop-2-enoylamino)phenyl]sulfonylpiperidin-4-yl]carbamate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.6000	uM
tert-butyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	4.9000	uM
ethyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.0000	uM
(6-methoxycarbonylnaphthalen-2-yl)methyl 4-[2-[(2-bromoacetyl)amino]acetyl]piperazine-1-carboxylate	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	5.0000	uM
(2-methylphenyl)methyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.1000	uM
benzyl 4-[2-(prop-2-enoylamino)pyrimidin-5-yl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.1000	uM
N-[4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.4000	uM
N-[4-[4-(4,4-difluoropiperidine-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.4000	uM
N-[4-[4-(cyclopentanecarbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.6000	uM
N-[5-[4-(adamantane-1-carbonyl)piperazin-1-yl]sulfonyl-2-pyridinyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.6000	uM
N-[4-[4-[3-(trifluoromethyl)-2-pyridinyl]piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	5.9000	uM
N-[4-[4-(cyclopropanecarbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.0000	uM
(2-chlorophenyl)methyl 4-[4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.1000	uM
N-[4-(4-phenylpiperazin-1-yl)sulfonylphenyl]prop-2-enamide	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.1000	uM
N-[6-[imidazo[1,2-d][1,2,4]thiadiazol-3-yl(methyl)amino]hexyl]-2-nitrobenzenesulfonamide	240715: Inhibitory concentration against guinea pig liver transglutaminase	ic50	6.2000	uM
benzyl 4-[[6-(prop-2-enoylamino)-3-pyridinyl]sulfonyl]piperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.4000	uM
benzyl 4-[4-(4-diazo-3-oxobutyl)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.4000	uM
tert-butyl 4-[2-methyl-4-(prop-2-enoylamino)phenyl]sulfonylpiperazine-1-carboxylate	683885: Inhibition of human recombinant TG1 by fluorescent transamidation assay	ic50	6.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, decreases expression	8
sodium arsenite	affects cotreatment, increases expression, decreases reaction, decreases expression, increases abundance	5
Estradiol	affects cotreatment, decreases expression	3
Tetrachlorodibenzodioxin	decreases reaction, increases expression	3
sodium arsenate	increases expression, decreases reaction, decreases expression, increases abundance, affects cotreatment	2
Alitretinoin	decreases expression	2
Arsenic	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
4-oxoretinoic acid	decreases expression	1
bisphenol A	decreases expression	1
lead acetate	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment, affects localization	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	decreases expression, increases abundance	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
cupric chloride	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	decreases expression	1
avobenzone	decreases expression	1
antimonite	decreases expression, increases abundance	1
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
NPS R-467	increases reaction, increases expression	1
SR 11238	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2091158	Binding	Inhibition of human recombinant TG1 by fluorescent transamidation assay	Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington’s disease. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation