RC3H1

Summary

RC3H1 (ring finger and CCCH-type domains 1, HGNC:29434) is a protein-coding gene on chromosome 1q25.1, encoding Roquin-1 (Q5TC82). Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3’-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs.

This gene encodes a protein containing RING-type and C3H1-type zinc finger motifs. The encoded protein recognizes and binds to a constitutive decay element (CDE) in the 3’ UTR of mRNAs, leading to mRNA deadenylation and degradation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 149041 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemophagocytic lymphohistiocytosis, familial, 6 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 120 total — 3 pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_172071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29434
Approved symbol	RC3H1
Name	ring finger and CCCH-type domains 1
Location	1q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA2025, roquin, RP5-1198E17.5, RNF198
Ensembl gene	ENSG00000135870
Ensembl biotype	protein_coding
OMIM	609424
Entrez	149041

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 retained_intron

ENST00000367694, ENST00000367696, ENST00000479099, ENST00000484867, ENST00000531594, ENST00000892872, ENST00000957921

RefSeq mRNA: 4 — MANE Select: NM_172071 NM_001300850, NM_001300851, NM_001300852, NM_172071

CCDS: CCDS30940, CCDS72987

Canonical transcript exons

ENST00000367696 — 20 exons

Exon	Start	End
ENSE00000789912	173941265	173941380
ENSE00000789913	173943442	173943615
ENSE00000958696	173947369	173947582
ENSE00000958698	173946476	173946608
ENSE00001150310	173946746	173946836
ENSE00001150321	173951986	173952138
ENSE00001150326	173961077	173961244
ENSE00001150331	173961725	173962095
ENSE00001299815	173983418	173983657
ENSE00001301751	173964839	173965120
ENSE00001304102	173980809	173981009
ENSE00001307702	173972509	173972627
ENSE00001320494	173970505	173970617
ENSE00001323967	173984499	173984619
ENSE00001324389	173978488	173978620
ENSE00001330128	173963973	173964187
ENSE00001802142	173982727	173982902
ENSE00001878902	174022096	174022357
ENSE00001931588	173992755	173993135
ENSE00003897925	173931084	173938871

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 96.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2797 / max 327.2458, expressed in 1782 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15980	12.2797	1782

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	96.88	gold quality
upper leg skin	UBERON:0004262	95.52	gold quality
ileal mucosa	UBERON:0000331	95.22	gold quality
deltoid	UBERON:0001476	95.19	gold quality
oviduct epithelium	UBERON:0004804	94.57	gold quality
buccal mucosa cell	CL:0002336	94.34	gold quality
skin of hip	UBERON:0001554	94.27	gold quality
upper arm skin	UBERON:0004263	94.04	gold quality
epithelial cell of pancreas	CL:0000083	93.66	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.36	gold quality
trabecular bone tissue	UBERON:0002483	92.41	gold quality
middle temporal gyrus	UBERON:0002771	92.16	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.09	gold quality
esophagus squamous epithelium	UBERON:0006920	92.02	gold quality
bronchial epithelial cell	CL:0002328	91.35	gold quality
oral cavity	UBERON:0000167	91.34	gold quality
quadriceps femoris	UBERON:0001377	91.31	gold quality
colonic epithelium	UBERON:0000397	91.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.20	gold quality
bone marrow cell	CL:0002092	90.97	gold quality
bronchus	UBERON:0002185	90.93	gold quality
cauda epididymis	UBERON:0004360	90.87	gold quality
vastus lateralis	UBERON:0001379	90.83	gold quality
endothelial cell	CL:0000115	90.81	silver quality
cartilage tissue	UBERON:0002418	90.68	gold quality
bone marrow	UBERON:0002371	90.42	gold quality
amniotic fluid	UBERON:0000173	90.35	gold quality
layer of synovial tissue	UBERON:0007616	90.34	gold quality
caput epididymis	UBERON:0004358	90.17	gold quality
thymus	UBERON:0002370	90.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-110499	no	1076.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2, REL, STAT1, STAT3

miRNA regulators (miRDB)

476 targeting RC3H1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4534	99.99	66.58	1907

Literature-anchored findings (GeneRIF, showing 20)

• Excessive interferon (IFN)-gamma signaling promotes accumulation of Roquin-mutated, short-lived effector-like CD8+ T cells in autoimmune-prone transgenic mice. (PMID:22685317)
• Roquin-mediated degradation of HMGXB3 and IL6 mRNAs in human cells, demonstrates the importance of both binding sites for mRNA decay. (PMID:25026078)
• Roquin binding to target mRNAs involves a winged helix-turn-helix motif. (PMID:25504471)
• decreased expression in colon biopsies of Crohn’s disease patients but not in ulcerative colitis patients (PMID:25886994)
• In this review we summarize current progress regarding the specific characteristics of sequences and structures in the 3’ untranslated regions of mRNAs that are recognized by tristetraproline, Roquins, and Regnase-1. (PMID:25955820)
• Findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation. (PMID:26000482)
• A distinct, sequence-induced conformation is required for recognition of the constitutive decay element RNA by Roquin. (PMID:26165594)
• RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IkappaB kinase and NF-kappaB activities. (PMID:26170170)
• Roquin-1 and roquin-2 proteins function redundantly in mRNA degradation. (PMID:26249698)
• Crystal structures, small-angle X-ray scattering, and E2 profiling revealed that while the two paralogs are highly homologous, RC3H2 and RC3H1 are different in their structures and functions. (PMID:26489670)
• RC3H1 is a multifunctional regulator of immune homeostasis. (Review) (PMID:26673963)
• Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. (PMID:29352114)
• analysis of previously unknown cis-regulatory elements in Roquin protein (PMID:30295819)
• Transcriptome profiling revealed Roquin-dependent global downregulation of proinflammatory cytokines and antiviral genes in by human cytomegalovirus infected cells. IFN regulatory factor 1 (IRF1), a master transcriptional activator of immune responses, identified as a Roquin target gene. Roquin reduces IRF1 expression by directly binding to its mRNA, thereby enabling suppression of a variety of antiviral genes. (PMID:31451648)
• MAP7 interacts with RC3H1 and cooperatively regulate cell-cycle progression of cervical cancer cells via activating the NF-kappaB signaling. (PMID:32446391)
• Structural basis for the recognition of transiently structured AU-rich elements by Roquin. (PMID:32491174)
• Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle-promoting genes. (PMID:33228782)
• Dynamic Regulation of the Nexus Between Stress Granules, Roquin, and Regnase-1 Underlies the Molecular Pathogenesis of Warfare Vesicants. (PMID:35082795)
• miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1. (PMID:35999072)
• Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells. (PMID:36920923)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rc3h1a	ENSDARG00000062550
danio_rerio	rc3h1b	ENSDARG00000063182
mus_musculus	Rc3h1	ENSMUSG00000040423
rattus_norvegicus	Rc3h1	ENSRNOG00000002750
drosophila_melanogaster	roq	FBGN0036621

Paralogs (5): RC3H2 (ENSG00000056586), RNF227 (ENSG00000179859), RNF182 (ENSG00000180537), RNF224 (ENSG00000233198), RNF228 (ENSG00000288658)

Protein

Protein identifiers

Roquin-1 — Q5TC82 (reviewed: Q5TC82)

Alternative names: RING finger and C3H zinc finger protein 1, RING finger and CCCH-type zinc finger domain-containing protein 1, RING finger protein 198

All UniProt accessions (1): Q5TC82

UniProt curated annotations — full annotation on UniProt →

Function. Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3’-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs. Cleaves translationally inactive mRNAs harboring a stem-loop (SL), often located in their 3’-UTRs, during the early phase of inflammation in a helicase UPF1-independent manner. Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs. In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation. Recognizes and binds mRNAs containing a hexaloop stem-loop motif, called alternative decay element (ADE). Together with ZC3H12A, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3’UTR. Able to interact with double-stranded RNA (dsRNA). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3’ end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression. Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2A, UBE2B, UBE2D2, UBE2F, UBE2G1, UBE2G2 and UBE2L3 and produces polyubiquitin chains. Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains.

Subunit / interactions. Able to homodimerize. Interacts with DDX6 and EDC4. Interacts with CCR4-NOT deadenylase complex. Interacts with RC3H1; the interaction is RNA independent.

Subcellular location. Cytoplasm. P-body. Cytoplasmic granule.

Tissue specificity. Widely expressed. Expressed at higher level in cerebellum, spleen, ovary and liver.

Post-translational modifications. Proteolytically cleaved after Arg-510 and Arg-579 by MALT1 in activated CD4(+) T cells; cleavage at Arg-510 and Arg-579 is critical for promoting RC3H1 degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling Th17 cell differentiation.

Disease relevance. Immune dysregulation and systemic hyperinflammation syndrome (IMDYSHI) [MIM:618998] An autosomal recessive disorder characterized by systemic hyperinflammation in the absence of an infectious agent or autoimmune trigger. Features include lymphadenopathy, hepatosplenomegaly, recurrent fever, and laboratory evidence of immune dysregulation with abnormal immune cell populations and increased serum levels of inflammatory cytokines. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RING-type zinc finger is required for proper localization to stress granules, but not to P-bodies. The ROQ region is required for CDE RNA-binding. Has 2 separate RNA-binding sites, one for CDE RNA and the other for dsRNA, both sites are important for mRNA decay. ADE RNA-binding involves an extended binding surface on the ROQ region with a number of additional residues compared with the CDE RNA. It may also be involved in localization to stress granules. HEPN (higher eukaryotes and prokaryotes nucleotide-binding) are observed in both N- and C-terminal sides of ROQ domain with 3D structure even if they are poredcted on the basis of sequence.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5TC82-1	1	yes
Q5TC82-2	2

RefSeq proteins (4): NP_001287779, NP_001287780, NP_001287781, NP_742068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR036855	Znf_CCCH_sf	Homologous_superfamily
IPR041523	ROQ_II	Domain
IPR048575	Roquin_1_2-like_ROQ	Domain
IPR052249	Roquin_domain	Family

Pfam: PF14634, PF18386, PF21206

UniProt features (70 total): helix 21, mutagenesis site 8, binding site 7, region of interest 7, strand 6, modified residue 5, compositionally biased region 4, turn 3, zinc finger region 2, site 2, splice variant 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4YWQ	X-RAY DIFFRACTION	1.7
4QIK	X-RAY DIFFRACTION	1.9
4ULW	X-RAY DIFFRACTION	1.91
3X1O	X-RAY DIFFRACTION	2.2
4QIL	X-RAY DIFFRACTION	2.9
8RHS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TC82-F1	61.65	0.30

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 (2): 510 (cleavage; by malt1); 579 (cleavage; by malt1)

Ligand- & substrate-binding residues (7): 14; 17; 33; 35; 38; 50; 53

Post-translational modifications (5): 462, 531, 535, 863, 1110

Mutagenesis-validated functional residues (8):

Position	Phenotype
135–136	no effect on cde rna-binding but abolishes dsrna binding; when associated with e-164 or a-322-323-a.
164	no effect on cde rna-binding but abolishes dsrna binding; when associated with 135-e-e-136.
219–220	strongly decreases binding to rna containing cde stem-loop motifs. abolishes binding to rna containing cde stem-loop mot
239–240	abolishes cde rna-binding but no effect on dsrna binding.
247–251	abolishes cde rna-binding but no effect on dsrna binding.
259–260	strongly decreases binding to rna containing cde stem-loop motifs. abolishes binding to rna containing cde stem-loop mot
318–319	slightly reduces stem-loop rna and dsrna binding.
322–323	no effect on cde rna-binding but abolishes dsrna binding; when associated with 135-e-e-136.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 408 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, AAGCAAT_MIR137, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_P_BODY_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION

GO Biological Process (30): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), protein polyubiquitination (GO:0000209), nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), nuclear-transcribed mRNA catabolic process (GO:0000956), B cell homeostasis (GO:0001782), regulation of germinal center formation (GO:0002634), negative regulation of germinal center formation (GO:0002635), ubiquitin-dependent protein catabolic process (GO:0006511), post-transcriptional regulation of gene expression (GO:0010608), negative regulation of B cell proliferation (GO:0030889), P-body assembly (GO:0033962), T cell proliferation (GO:0042098), T cell homeostasis (GO:0043029), regulation of mRNA stability (GO:0043488), negative regulation of T-helper cell differentiation (GO:0045623), negative regulation of activated T cell proliferation (GO:0046007), lymph node development (GO:0048535), spleen development (GO:0048536), T cell receptor signaling pathway (GO:0050852), regulation of T cell receptor signaling pathway (GO:0050856), 3’-UTR-mediated mRNA destabilization (GO:0061158), T follicular helper cell differentiation (GO:0061470), cellular response to interleukin-1 (GO:0071347), regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900151), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), negative regulation of T-helper 17 cell differentiation (GO:2000320), regulation of miRNA metabolic process (GO:2000628), regulation of gene expression (GO:0010468), protein ubiquitination (GO:0016567), positive regulation of mRNA catabolic process (GO:0061014)

GO Molecular Function (13): RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), mRNA binding (GO:0003729), mRNA 3’-UTR binding (GO:0003730), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), miRNA binding (GO:0035198), RNA stem-loop binding (GO:0035613), ubiquitin protein ligase activity (GO:0061630), CCR4-NOT complex binding (GO:1905762), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): P-body (GO:0000932), cytoplasmic stress granule (GO:0010494), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA binding	3
nuclear-transcribed mRNA catabolic process	2
protein ubiquitination	2
lymphocyte homeostasis	2
germinal center formation	2
hematopoietic or lymphoid organ development	2
cytoplasmic ribonucleoprotein granule	2
mRNA destabilization	1
mRNA catabolic process	1
regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of anatomical structure morphogenesis	1
regulation of germinal center formation	1
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
negative regulation of developmental process	1
modification-dependent protein catabolic process	1
regulation of gene expression	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of B cell activation	1
membraneless organelle assembly	1
T cell activation	1
lymphocyte proliferation	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
T-helper cell differentiation	1
negative regulation of CD4-positive, alpha-beta T cell differentiation	1
regulation of T-helper cell differentiation	1
negative regulation of immune response	1
negative regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
antigen receptor-mediated signaling pathway	1
T cell receptor signaling pathway	1
regulation of antigen receptor-mediated signaling pathway	1
nucleic acid binding	1
mRNA binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
regulatory RNA binding	1

Protein interactions and networks

STRING

2212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RC3H1	ICOS	Q9Y6W8	893
RC3H1	ZC3H12A	Q5D1E8	767
RC3H1	CNR2	P34972	687
RC3H1	CXCR5	P32302	668
RC3H1	CD28	P10747	610
RC3H1	NUFIP2	Q7Z417	604
RC3H1	B3GAT1	Q9P2W7	603
RC3H1	CNOT1	A5YKK6	601
RC3H1	ICOSLG	O75144	596
RC3H1	TNF	P01375	584
RC3H1	MALT1	Q9UDY8	570
RC3H1	A0A087X1L8	A0A087X1L8	548
RC3H1	ZFP36	P26651	547
RC3H1	AGO2	Q9UKV8	539
RC3H1	IL2	P01585	532

IntAct

23 interactions, top by confidence:

A	B	Type	Score
CEP135	RC3H1	psi-mi:“MI:0915”(physical association)	0.540
CEP135	RC3H1	psi-mi:“MI:0403”(colocalization)	0.540
Dlg4	RC3H1	psi-mi:“MI:0407”(direct interaction)	0.440
RC3H1	DDX6	psi-mi:“MI:2364”(proximity)	0.410
	RC3H1	psi-mi:“MI:0915”(physical association)	0.400
PB2	HAX1	psi-mi:“MI:0914”(association)	0.350
CEP135	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WWP2	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
WWP2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
FAM168A	CCDC85C	psi-mi:“MI:0914”(association)	0.350
Rc3h1	CNOT1	psi-mi:“MI:0914”(association)	0.350
Rc3h2	CNOT1	psi-mi:“MI:0914”(association)	0.350
AGO2	RC3H1	psi-mi:“MI:2364”(proximity)	0.270
CPEB1	CNOT1	psi-mi:“MI:2364”(proximity)	0.270
FASTKD2	MED19	psi-mi:“MI:2364”(proximity)	0.270
LIN28B	MEX3A	psi-mi:“MI:2364”(proximity)	0.270
RPS3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
SF3B4	MED19	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
TAF15	SBNO1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (900): TNF (Protein-RNA), Hmgxb3 (Protein-RNA), UBE2B (Reconstituted Complex), UBE2D2 (Reconstituted Complex), UBE2G2 (Reconstituted Complex), UBE2A (Reconstituted Complex), UBE2L3 (Reconstituted Complex), UBE2F (Reconstituted Complex), UBE2G1 (Reconstituted Complex), UBE2N (Reconstituted Complex), UBE2V1 (Reconstituted Complex), UBE2V2 (Reconstituted Complex), ACTG1 (Affinity Capture-MS), AKAP8L (Affinity Capture-MS), ALB (Affinity Capture-MS)

ESM2 similar proteins: A0JMF8, A2RSY1, A6QLW9, B1WAV2, B2GV50, O60271, O75069, O77627, P05412, P05627, P0C090, P17325, P22670, P48377, P48378, P48379, P48380, P48381, P56432, Q0V989, Q0V9K5, Q16656, Q32NR3, Q3KR73, Q499B3, Q49GP3, Q4R3I8, Q4R3Z4, Q4V872, Q4VGL6, Q58A65, Q5EAP5, Q5EY87, Q5RDR2, Q5RJA1, Q5TC82, Q62739, Q66IV1, Q6NRE7, Q6NUC6

Diamond homologs: O45962, P0C090, Q4VGL6, Q5TC82, Q6NUC6, Q9HBD1, Q11072, Q13049, Q8CH72, Q9T075, A5D8S5, D2H6Z0, D2H788, D3ZBM4, D4A723, E1C2W7, M0QZC1, O60858, P0CG21, Q32L60, Q3UP44, Q58EC8, Q5M7V1, Q68EV7, Q6GND7, Q6IMG5, Q6INB3, Q6VVB1, Q810I1, Q810I2, Q865W2, Q86UV6, Q86UV7, Q86XT4, Q8BG47, Q8C432, Q8N6D2, Q8N8N0, Q9CYB0, O54952

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
“CCR4-NOT complex”	“down-regulates quantity by repression”	RC3H1	“post transcriptional regulation”
Ub:E2	“up-regulates activity”	RC3H1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	92
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1321901	NC_000001.11:g.173912160_174154195del	Pathogenic
3247682	NC_000001.10:g.(?173873027)(173962123_?)del	Pathogenic
977475	NM_172071.4(RC3H1):c.2062C>T (p.Arg688Ter)	Pathogenic

SpliceAI

2638 predictions. Top by Δscore:

Variant	Effect	Δscore
1:173941260:TTTA:T	donor_loss	1.0000
1:173941261:TTA:T	donor_loss	1.0000
1:173941262:TA:T	donor_loss	1.0000
1:173941264:C:CG	donor_loss	1.0000
1:173941376:TTTTC:T	acceptor_gain	1.0000
1:173941377:TTTC:T	acceptor_gain	1.0000
1:173941378:TTC:T	acceptor_gain	1.0000
1:173941379:TC:T	acceptor_gain	1.0000
1:173941380:CCTT:C	acceptor_gain	1.0000
1:173941381:C:CA	acceptor_loss	1.0000
1:173941381:C:CC	acceptor_gain	1.0000
1:173941381:C:T	acceptor_gain	1.0000
1:173941382:T:C	acceptor_gain	1.0000
1:173941382:T:G	acceptor_loss	1.0000
1:173941382:T:TC	acceptor_gain	1.0000
1:173941383:T:C	acceptor_gain	1.0000
1:173941383:T:TC	acceptor_gain	1.0000
1:173946490:G:C	donor_gain	1.0000
1:173946741:CATA:C	donor_loss	1.0000
1:173946743:TA:T	donor_loss	1.0000
1:173946744:ACCT:A	donor_gain	1.0000
1:173946745:C:CG	donor_loss	1.0000
1:173946745:CCT:C	donor_gain	1.0000
1:173946745:CCTC:C	donor_gain	1.0000
1:173946833:TAAT:T	acceptor_gain	1.0000
1:173946835:AT:A	acceptor_gain	1.0000
1:173946836:TC:T	acceptor_loss	1.0000
1:173946837:C:CC	acceptor_gain	1.0000
1:173946837:CT:C	acceptor_loss	1.0000
1:173947364:CTTA:C	donor_loss	1.0000

AlphaMissense

7338 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:173970511:A:G	L443P	1.000
1:173970525:G:C	H438Q	1.000
1:173970525:G:T	H438Q	1.000
1:173970526:T:C	H438R	1.000
1:173970527:G:C	H438D	1.000
1:173970527:G:T	H438N	1.000
1:173970529:G:T	A437E	1.000
1:173970531:A:C	F436L	1.000
1:173970531:A:T	F436L	1.000
1:173970532:A:C	F436C	1.000
1:173970532:A:G	F436S	1.000
1:173970533:A:C	F436V	1.000
1:173970533:A:G	F436L	1.000
1:173970533:A:T	F436I	1.000
1:173970537:A:C	C434W	1.000
1:173970538:C:A	C434F	1.000
1:173970538:C:G	C434S	1.000
1:173970538:C:T	C434Y	1.000
1:173970539:A:C	C434G	1.000
1:173970539:A:G	C434R	1.000
1:173970539:A:T	C434S	1.000
1:173970551:G:T	R430S	1.000
1:173970555:G:C	C428W	1.000
1:173970556:C:A	C428F	1.000
1:173970556:C:G	C428S	1.000
1:173970556:C:T	C428Y	1.000
1:173970557:A:C	C428G	1.000
1:173970557:A:G	C428R	1.000
1:173970557:A:T	C428S	1.000
1:173970582:A:C	C419W	1.000

dbSNP variants (sampled 300 via entrez): RS1000047620 (1:173961015 T>A,C), RS1000049911 (1:174005872 T>C), RS1000132444 (1:173951169 T>C), RS1000142900 (1:174006123 C>A,T), RS1000151764 (1:173944487 C>T), RS1000189822 (1:173954336 A>G), RS1000212180 (1:173960880 A>C), RS1000218066 (1:173954024 G>A), RS1000221156 (1:173954803 A>C), RS1000283851 (1:174000938 A>G), RS1000287344 (1:173948073 G>A), RS1000306335 (1:173992619 T>C), RS1000323607 (1:173988277 T>C), RS1000339988 (1:174012420 A>T), RS1000458926 (1:173986985 T>C)

Disease associations

OMIM: gene MIM:609424 | disease phenotypes: MIM:613118, MIM:618998

GenCC curated gene-disease

Disease	Classification	Inheritance
hemophagocytic lymphohistiocytosis, familial, 6	Moderate	Autosomal recessive
inborn error of immunity	Limited	Autosomal dominant

Mondo (3): hereditary antithrombin deficiency (MONDO:0013144), hemophagocytic lymphohistiocytosis, familial, 6 (MONDO:0033557), inborn error of immunity (MONDO:0003778)

Orphanet (1): Hereditary thrombophilia due to congenital antithrombin deficiency (Orphanet:82)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000465	Webbed neck
HP:0001256	Mild intellectual disability
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0003281	Increased circulating ferritin concentration
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0011900	Hypofibrinogenemia
HP:0012115	Hepatitis
HP:0012156	Hemophagocytosis
HP:0012312	Decreased total monocyte count
HP:0025808	Decreased natural killer cell-induced killing of target cells
HP:0030371	Increased naive B cell proportion
HP:0030948	Elevated gamma-glutamyltransferase level
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0032323	Periodic fever
HP:0033833	Elevated circulating sCD25 concentration
HP:0034447	Increased circulating interleukin 18 concentration
HP:6000239	Elevated circulating tumor necrosis factor alpha concentration
HP:6000374	Increased circulating interleukin 1beta concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012490_222	Femur bone mineral density x serum urate levels interaction	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020152	Antithrombin III Deficiency	C15.378.100.100.075; C15.378.147.150; C15.378.925.075; C16.320.099.075
D007153	Immunologic Deficiency Syndromes	C20.673

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
Cyclosporine	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol A	affects cotreatment, decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
coumarin	increases phosphorylation	1
bisphenol S	decreases expression, affects cotreatment	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Gold	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Methotrexate	decreases expression	1
Ribonucleotides	affects binding	1
Theophylline	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Zinc	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2IT	HAP1 RC3H1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT02278575	PHASE4	WITHDRAWN	Atenativ Effect on Uterine Blood Flow and Preeclampsia
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT00110513	PHASE3	COMPLETED	Recombinant Human Antithrombin (rhAT) in Patients With Hereditary Antithrombin Deficiency Undergoing Surgery or Delivery
NCT04918173	PHASE3	RECRUITING	Efficacy of Atenativ in Patients With Congenital Antithrombin Deficiency Undergoing Surgery or Delivery
NCT06096116	PHASE3	RECRUITING	Phase 3 Study on the Efficacy and Safety of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID
NCT01856582	PHASE2	TERMINATED	CD34+ Stem Cell Infusion to Augment Graft Function
NCT06199427	PHASE2	RECRUITING	PTCy and and Ruxolitinib for GVHD Prophylaxis After HSCT With Thymoglobulin in Conditioning Regimen in Patients With Inborn Errors of Immunity
NCT00823082	PHASE2	COMPLETED	Use of Antithrombin in Cardiac Surgery With Cardiopulmonary Bypass
NCT04899232	PHASE2	TERMINATED	Antithrombin III in Infectious Disease Caused by COVID-19
NCT00938288	PHASE1	COMPLETED	A Study of KW-3357 in Congenital Antithrombin Deficiency
NCT00001158	Not specified	COMPLETED	Studies of the Immune Response in Normal Subjects and Patients With Disorders of the Immune System
NCT00001336	Not specified	COMPLETED	In Vitro Studies of Immunological and Stem Cell Function in Peripheral Blood Mononuclear Cells in Patients
NCT00001788	Not specified	TERMINATED	Genetic Basis of Primary Immunodeficiencies
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006131	Not specified	COMPLETED	Randomized Study of Two Doses of Oral Valacyclovir in Immunocompromised Patients With Uncomplicated Herpes Zoster
NCT01150240	Not specified	UNKNOWN	Clinical and Laboratory Online Patient- and Research Database for Primary Immunodeficiencies in Switzerland
NCT01727895	Not specified	COMPLETED	Effects of Orally Administered Beta-glucan on Leukocyte Function in Humans
NCT02176239	Not specified	COMPLETED	Monitoring of 5% Treatment Naïve Intravenous Immunoglobulin (IVIg) Primary Immunodeficiency Disease (PIDD) Patients Using the CareExchange® System: A Pilot Study Using 5% Gammaplex® IVIg in the Home Setting
NCT02417740	Not specified	RECRUITING	Natural History of Noncirrhotic Portal Hypertension
NCT02554630	Not specified	COMPLETED	Novel Mechanisms and Approaches to Treat Neonatal Sepsis
NCT02630082	Not specified	COMPLETED	Feasibility of Measuring Immune Resp, Activation in Foreskin/Mucosa in HIV-, Uncircumcised High-HIV-risk MSM, Lima Peru