RCHY1

Summary

RCHY1 (ring finger and CHY zinc finger domain containing 1, HGNC:17479) is a protein-coding gene on chromosome 4q21.1, encoding RING finger and CHY zinc finger domain-containing protein 1 (Q96PM5). E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins, including p53/TP53, TP73, HDAC1 and CDKN1B.

The protein encoded by this gene has ubiquitin ligase activity. It mediates E3-dependent ubiquitination and proteasomal degradation of target proteins, including tumor protein 53, histone deacetylase 1, and cyclin-dependent kinase inhibitor 1B, thus regulating their levels and cell cycle progression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 25898 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 41 total — 1 pathogenic
• MANE Select transcript: NM_015436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17479
Approved symbol	RCHY1
Name	ring finger and CHY zinc finger domain containing 1
Location	4q21.1
Locus type	gene with protein product
Status	Approved
Aliases	CHIMP, DKFZp586C1620, PRO1996, RNF199, ARNIP, PIRH2, ZCHY
Ensembl gene	ENSG00000163743
Ensembl biotype	protein_coding
OMIM	607680
Entrez	25898

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000324439, ENST00000380840, ENST00000504085, ENST00000505105, ENST00000505514, ENST00000507014, ENST00000512567, ENST00000512706, ENST00000513083, ENST00000513257, ENST00000513909, ENST00000514021, ENST00000514589, ENST00000906838, ENST00000906839, ENST00000906840, ENST00000906841, ENST00000906842, ENST00000906843, ENST00000906844, ENST00000906845, ENST00000915594

RefSeq mRNA: 8 — MANE Select: NM_015436 NM_001009922, NM_001278536, NM_001278537, NM_001278538, NM_001278539, NM_001387136, NM_001387137, NM_015436

CCDS: CCDS34012, CCDS3567, CCDS63990, CCDS63991, CCDS63992

Canonical transcript exons

ENST00000324439 — 9 exons

Exon	Start	End
ENSE00001946767	75479033	75482666
ENSE00002020453	75514197	75514403
ENSE00003461874	75509177	75509296
ENSE00003517779	75494101	75494179
ENSE00003522288	75508820	75508935
ENSE00003537471	75491724	75491782
ENSE00003545527	75491889	75491933
ENSE00003616569	75491611	75491637
ENSE00003624968	75490581	75490701

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.6596 / max 172.2434, expressed in 1742 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52579	4.9556	1627
52580	4.7041	1309

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.03	gold quality
secondary oocyte	CL:0000655	97.07	gold quality
endothelial cell	CL:0000115	96.73	gold quality
male germ cell	CL:0000015	96.62	gold quality
oocyte	CL:0000023	94.95	gold quality
germinal epithelium of ovary	UBERON:0001304	94.78	gold quality
choroid plexus epithelium	UBERON:0003911	94.58	gold quality
islet of Langerhans	UBERON:0000006	94.13	gold quality
cortical plate	UBERON:0005343	93.39	gold quality
biceps brachii	UBERON:0001507	93.37	gold quality
heart right ventricle	UBERON:0002080	93.37	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.19	gold quality
parietal pleura	UBERON:0002400	93.08	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.93	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.84	gold quality
palpebral conjunctiva	UBERON:0001812	92.75	gold quality
monocyte	CL:0000576	92.59	gold quality
pigmented layer of retina	UBERON:0001782	92.59	gold quality
mononuclear cell	CL:0000842	92.50	gold quality
jejunal mucosa	UBERON:0000399	92.41	gold quality
pleura	UBERON:0000977	92.41	gold quality
renal glomerulus	UBERON:0000074	92.37	gold quality
nephron tubule	UBERON:0001231	92.31	gold quality
colonic mucosa	UBERON:0000317	92.23	gold quality
leukocyte	CL:0000738	92.18	gold quality
amniotic fluid	UBERON:0000173	92.08	gold quality
visceral pleura	UBERON:0002401	92.07	gold quality
adult organism	UBERON:0007023	91.89	gold quality
metanephric glomerulus	UBERON:0004736	91.85	gold quality
esophagus squamous epithelium	UBERON:0006920	91.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	504.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, TP53, TP73

miRNA regulators (miRDB)

146 targeting RCHY1, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 40)

• cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity [androgen-receptor N-terminal-interacting protein; hARNIP] (PMID:12200228)
• Pirh2 (ZNF363), a gene regulated by p53, encodes a RING-H2 domain-containing protein with intrinsic ubiquitin-protein ligase activity. Pirh2 protein physically interacts with p53 and promotes ubiquitination and degradation of p53 independently of Mdm2. (PMID:12654245)
• This protein is a p53-induced ubiquitin-protein ligase which promotes p53 degradation. (PMID:12654245)
• These results are consistent with the hypothesis that increased Pirh2 expression affects lung tumorigenesis by reducing p53 activity. (PMID:15547185)
• Human PIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer. (PMID:16914734)
• Study evaluated Pirh2, MDM2, p53 and p21 expression after DNA damage using cancer cell lines with wildtype, mutant and null p53 and found that unlike MDM2, Pirh2 expression was not affected by wildtype p53 in the cancer cells. (PMID:16934800)
• phosphorylation of Pirh2 may act as a fine-tuning to maintain the balance of p53-Pirh2 autoregulatory feedback loop, which facilitates the tight regulation of p53 stability and tumor suppression (PMID:17568776)
• PIRH2 functions as a regulator for COP I complex. (PMID:17721809)
• Given the importance of Pirh2 in regulating p53 stability, its interaction with PLAGL2 may provide valuable therapeutic targets in treating Pirh2-overexpression malignancies. (PMID:17950244)
• Pirh2 acts as a negative regulator of p27(Kip1) function by promoting ubiquitin-dependent proteasomal degradation (PMID:18006823)
• The authors show that Pirh2-p53 interaction is dependent on the C-terminal zinc binding module of Pirh2, which binds to the tetramerization domain of p53. (PMID:19043414)
• The RCHY1 protein was displayed an unexpected role in regulating the organization of the network of K8/18 keratin filaments. (PMID:19282868)
• Pirh2 overexpression may have an important role in the development and maintenance of head and neck squamous cell carcinoma at least partially through p27 degradation (PMID:19445020)
• Pirh2 ubiquitin ligase has two novel isoforms that negatively regulate p53 independent of RING finger domains (PMID:19483087)
• increased expression of PIRH2 was correlated with poor survival in patients with hepatocellular carcinoma; PIRH2 is a novel prognostic marker for hepatocellular carcinoma (PMID:19551892)
• expression of measles virus antigens in non-small cell lung carcinoma is associated with expression of Pirh2. The presence of Pirh2 itself was associated with improved survival. (PMID:19895323)
• PRL-3, like PRL-1, can negatively regulate p53 via the activation of PIRH2 and MDM2 in cancer cells. (PMID:19945467)
• found that DNA polymerase eta is recruited by Pirh2 and degraded by 20S proteasome in a ubiquitin-independent manner. (PMID:20008555)
• MDM2, MDMX, Pirh2 and COP1 might inhibit p53 activity synergistically in vivo. (PMID:20333547)
• low level of expression of hPirh2 was found both at transcriptional and translational level in human hepatocellular carcinoma (HCC) when compared to non-cancerous tissue. The protein shows no ubiquitin protein ligase activity. (PMID:20452352)
• SCYL1-BP1 can be ubiquitinated and degraded by Pirh2 but not by MDM2, which suggests that SCYL1-BP1 can be regulated by Pirh2. (PMID:20598683)
• This comprehensive analysis of the Pirh2 and Mdm2 RING domains provides structural and mechanistic insight into p53 regulation by its E3 ligases. (PMID:21084285)
• Our results suggest that Pirh2 mediates the degradation of p27(Kip1) and participates in cell proliferation in human hepatocellular carcinoma (PMID:21236467)
• identified a novel Pirh2-interacting protein, AIG1, by yeast two-hybrid screening and confirmed its interaction with p53 both in vitro and in vivo (PMID:21622095)
• Data show that Pirh2 monoubiquitinates PolH at one of multiple lysine residues, and that monoubiquitination of PolH inhibits its ability to interact with PCNA and bypass UV-induced lesions, leading to decreased viability. (PMID:21791603)
• Pirh2 promotes the proteasomal turnover of TAp73, and thus targeting Pirh2 to restore TAp73-mediated growth suppression in p53-deficient tumors may be developed as a novel anti-cancer strategy. (PMID:21852228)
• low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients’ survival (PMID:22125490)
• suggested that the interaction of SCYL1BP1/Pirh2 could accelerate Pirh2 degradation through an ubiquitin-dependent pathway. SCYL1BP1 may function as an important tumor suppressor gene in HCC development (PMID:22570270)
• Compared to full-length PIRH2A, PIRH2E lacks amino acids 235-261, while PIRH2F is missing C-terminal amino acids 227-261 and both isoforms harbor the RING domain. (PMID:22766706)
• Pirh2 has a physiologically relevant role in keratinocyte differentiation through the posttranslational modification of p63 protein. (PMID:23235527)
• Findings indicate that PIRH2 has central roles in the ubiquitylation of Chk2 and its turnover and in the regulation of its function. (PMID:23449389)
• Overexpression of Pirh2 decreased the replication of prototype foamy virus, whereas knockdown of Pirh2 with specific siRNA increased PFV replication. (PMID:25848801)
• The Hoxa2-mediated decay of RCHY1 involves both the 19S and 20S proteasome complexes (PMID:26496426)
• Tumor suppressor p63 regulates expression of ubiquitin ligase PIRH2. (PMID:26995965)
• Decrease of PIRH2 expression in the breast cancer cell line MDA-MB-231 resulted in reduced tumor cell growth via the inhibition of cell proliferation and the interruption of cell cycle transition. (PMID:27393961)
• Data indicate cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PL(pro)), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. (PMID:27519799)
• High Pirh2 expression was positively correlated with high tumor grade in brain glioma specimens. (PMID:28258514)
• p27 and its cognate ubiquitin ligases, Skp2/KPC/Pirh2, are specifically involved in determining the clinical profiles of lung carcinomas. (PMID:28601655)
• By forming a complex with Twist1 and the E3 ligase Pirh2, WT p53 promotes the ubiquitination and proteasomal degradation of Twist1, thus inhibiting EMT and maintaining the epithelial phenotype. The ability of p53 to induce Twist1 degradation is abrogated when p53 is mutated. (PMID:30131448)
• higher expression level of Naa10 and lower expression level of Pirh2 in oral squamous cell carcinoma tissues than adjacent normal tissues; expression of Naa10p is negatively correlated with that of Pirh2 (PMID:31134698)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rchy1	ENSDARG00000016710
mus_musculus	Rchy1	ENSMUSG00000029397
drosophila_melanogaster	Rchy1	FBGN0031816

Protein

Protein identifiers

RING finger and CHY zinc finger domain-containing protein 1 — Q96PM5 (reviewed: Q96PM5)

Alternative names: Androgen receptor N-terminal-interacting protein, CH-rich-interacting match with PLAG1, E3 ubiquitin-protein ligase Pirh2, RING finger protein 199, RING-type E3 ubiquitin transferase RCHY1, Zinc finger protein 363, p53-induced RING-H2 protein

All UniProt accessions (3): Q96PM5, D6RAF6, H0YAI4

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins, including p53/TP53, TP73, HDAC1 and CDKN1B. Mediates ubiquitination and degradation of p53/TP53; preferentially acts on tetrameric p53/TP53. Catalyzes monoubiquitinates the translesion DNA polymerase POLH. Involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: RCHY1 acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation. Has no E3 ubiquitin-protein ligase activity.

Subunit / interactions. Monomer and homodimer. Interacts with AR, MDM2, KAT5, PLAG1, PLAGL2, COPE, UBE2D2 and GORAB/NTKLBP1.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Post-translational modifications. Subject to ubiquitination and proteasomal degradation. Interaction with PLAGL2 or KAT5 enhances protein stability.

Induction. Up-regulated during the S phase of the cell cycle. Expressed at low levels during G phase. Down-regulated in hepatocellular carcinoma.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Gene prediction based on partial mRNA data.

Isoforms (8)

UniProt ID	Names	Canonical?
Q96PM5-1	1, A	yes
Q96PM5-2	2, B
Q96PM5-3	3, C
Q96PM5-4	4, Pirh2b
Q96PM5-5	5, Pirh2D
Q96PM5-6	6
Q96PM5-7	7
Q96PM5-8	8

RefSeq proteins (8): NP_001009922, NP_001265465, NP_001265466, NP_001265467, NP_001265468, NP_001374065, NP_001374066, NP_056251* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR008913	Znf_CHY	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017921	Znf_CTCHY	Domain
IPR037274	Znf_CHY_sf	Homologous_superfamily
IPR037275	Znf_CTCHY_sf	Homologous_superfamily
IPR039512	RCHY1_zinc-ribbon	Domain

Pfam: PF05495, PF13639, PF14599

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (76 total): binding site 24, strand 18, turn 11, splice variant 7, helix 6, zinc finger region 3, sequence conflict 3, mutagenesis site 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7YNX	X-RAY DIFFRACTION	2.3
2JRJ	SOLUTION NMR
2K2C	SOLUTION NMR
2K2D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PM5-F1	90.64	0.86

Functional residue map

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

Ligand- & substrate-binding residues (24): 44; 50; 62; 65; 75; 78; 87; 90; 101; 102; 105; 108 …

Post-translational modifications (1): 257

Mutagenesis-validated functional residues (2):

Position	Phenotype
176	abolishes e3 ubiquitin-protein ligase activity.
186	abolishes e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

MSigDB gene sets: 220 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_DNA_DAMAGE_TOLERANCE, MORF_HDAC2, GOBP_TRANSLATION, MUELLER_PLURINET, GOBP_ERROR_FREE_TRANSLESION_SYNTHESIS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_PROTEIN_AUTOUBIQUITINATION

GO Biological Process (7): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), positive regulation of protein ubiquitination (GO:0031398), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), protein autoubiquitination (GO:0051865), error-free translesion synthesis (GO:0070987), rescue of stalled cytosolic ribosome (GO:0072344)

GO Molecular Function (8): p53 binding (GO:0002039), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Class I MHC mediated antigen processing & presentation	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
cellular anatomical structure	3
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
translesion synthesis	1
cytoplasmic translational elongation	1
ribosome disassembly	1
protein binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1307 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCHY1	GORAB	Q5T7V8	944
RCHY1	TP53	P04637	897
RCHY1	SCYL1	Q96KG9	891
RCHY1	MDM2	Q00987	815
RCHY1	AR	P10275	780
RCHY1	UBE2D2	P51669	719
RCHY1	HUWE1	Q7Z6Z7	664
RCHY1	SH2D3C	Q8N5H7	653
RCHY1	RNF144B	Q7Z419	599
RCHY1	KAT5	Q92993	585
RCHY1	MDM4	O15151	576
RCHY1	USP7	Q93009	507
RCHY1	WWP1	Q9H0M0	507
RCHY1	AIG1	Q9NVV5	507
RCHY1	COP1	Q8NHY2	503

IntAct

140 interactions, top by confidence:

A	B	Type	Score
TP53	RCHY1	psi-mi:“MI:0407”(direct interaction)	0.890
TP53	RCHY1	psi-mi:“MI:0915”(physical association)	0.890
RCHY1	TP53	psi-mi:“MI:0915”(physical association)	0.890
TP53	RCHY1	psi-mi:“MI:0403”(colocalization)	0.890
UBASH3B	RCHY1	psi-mi:“MI:0915”(physical association)	0.780
RCHY1	UBASH3B	psi-mi:“MI:0915”(physical association)	0.780
RCHY1	KLHL41	psi-mi:“MI:0915”(physical association)	0.720
KLHL41	RCHY1	psi-mi:“MI:0915”(physical association)	0.720
NOTCH2NLA	RCHY1	psi-mi:“MI:0915”(physical association)	0.670
RCHY1	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.670
NLK	RCHY1	psi-mi:“MI:0915”(physical association)	0.630
RCHY1	NLK	psi-mi:“MI:0915”(physical association)	0.630
NLK	RCHY1	psi-mi:“MI:0403”(colocalization)	0.630
RCHY1	AIG1	psi-mi:“MI:0915”(physical association)	0.600

BioGRID (446): TP53 (Affinity Capture-Western), RCHY1 (Affinity Capture-Western), RCHY1 (Reconstituted Complex), RCHY1 (Two-hybrid), RCHY1 (Two-hybrid), RCHY1 (Two-hybrid), RCHY1 (Two-hybrid), ADAMTSL4 (Two-hybrid), WDR74 (Two-hybrid), SEMA4C (Two-hybrid), LIMS2 (Two-hybrid), KRTAP9-2 (Two-hybrid), UBASH3B (Two-hybrid), NOTCH2NL (Two-hybrid), RCHY1 (Affinity Capture-MS)

ESM2 similar proteins: A1KRE2, A5F6R2, B0B8K2, B0BA81, B1JTT6, B1YRN6, B4EBK9, B4RPW8, C3LNU9, C4LBX3, O14033, O83641, O84632, P0DC40, P0DC41, P14930, P36078, P65443, P65444, P75129, Q10LI1, Q1LTK5, Q22431, Q252M0, Q3KL68, Q5F5P1, Q5JL96, Q5L7A0, Q5R869, Q5WH73, Q5XAX5, Q6CIK2, Q7N400, Q824X8, Q87MS5, Q8D849, Q8GWF4, Q8P046, Q8VZK0, Q96PM5

Diamond homologs: F4HVS0, F4IDY5, O14099, Q10LI1, Q5JL96, Q6DIP3, Q6IRP0, Q7T0Q3, Q8LPQ5, Q8VZK0, Q96PM5, Q9CR50, Q9FFB6, Q9VHI7, Q9Y4L5, Q6NRX0

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CAMK2A	down-regulates	RCHY1	phosphorylation
CDK9	down-regulates	RCHY1	phosphorylation
Ub:E2	“up-regulates activity”	RCHY1	ubiquitination
RCHY1	“down-regulates quantity by destabilization”	COPE	polyubiquitination
RCHY1	“down-regulates activity”	POLH	monoubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oncogene Induced Senescence	5	33.6×	7e-05
Regulation of TP53 Degradation	5	29.3×	9e-05
CLEC7A (Dectin-1) signaling	5	14.3×	1e-03
Intracellular signaling by second messengers	6	11.0×	9e-04
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	5	10.7×	2e-03
Oxidative Stress Induced Senescence	5	9.1×	3e-03
Diseases of signal transduction by growth factor receptors and second messengers	6	6.8×	3e-03
Ub-specific processing proteases	6	6.4×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	20
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4070972	NM_015436.4(RCHY1):c.157G>A (p.Asp53Asn)	Pathogenic

SpliceAI

1378 predictions. Top by Δscore:

Variant	Effect	Δscore
4:75482524:A:AC	donor_gain	1.0000
4:75482525:C:CC	donor_gain	1.0000
4:75490572:TCTAC:T	donor_loss	1.0000
4:75490573:CTACT:C	donor_loss	1.0000
4:75490574:TAC:T	donor_loss	1.0000
4:75490575:ACT:A	donor_loss	1.0000
4:75490576:CTC:C	donor_loss	1.0000
4:75490577:TCACA:T	donor_loss	1.0000
4:75490578:C:CC	donor_loss	1.0000
4:75490579:A:AC	donor_gain	1.0000
4:75490579:ACAT:A	donor_gain	1.0000
4:75490579:ACATC:A	donor_gain	1.0000
4:75490580:C:CA	donor_gain	1.0000
4:75490580:CA:C	donor_gain	1.0000
4:75490580:CAT:C	donor_gain	1.0000
4:75490580:CATC:C	donor_gain	1.0000
4:75490580:CATCC:C	donor_gain	1.0000
4:75490700:CT:C	acceptor_gain	1.0000
4:75490701:TC:T	acceptor_loss	1.0000
4:75490702:C:CC	acceptor_gain	1.0000
4:75490702:CT:C	acceptor_loss	1.0000
4:75490703:T:C	acceptor_loss	1.0000
4:75491609:A:AC	donor_gain	1.0000
4:75491610:C:CC	donor_gain	1.0000
4:75491610:CT:C	donor_gain	1.0000
4:75491635:GTTC:G	acceptor_loss	1.0000
4:75491636:TTCTG:T	acceptor_loss	1.0000
4:75491637:TCTG:T	acceptor_loss	1.0000
4:75491638:C:CC	acceptor_gain	1.0000
4:75491639:T:A	acceptor_loss	1.0000

AlphaMissense

1747 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:75482659:C:G	C222S	0.999
4:75482660:A:T	C222S	0.999
4:75491906:A:G	C145R	0.999
4:75494179:C:A	R109S	0.999
4:75494179:C:G	R109S	0.999
4:75508820:C:A	R109M	0.999
4:75508820:C:G	R109T	0.999
4:75508823:C:G	C108S	0.999
4:75508824:A:T	C108S	0.999
4:75482660:A:G	C222R	0.998
4:75490691:A:G	C183R	0.998
4:75491728:G:C	H169D	0.998
4:75491728:G:T	H169N	0.998
4:75491735:A:C	H166Q	0.998
4:75491735:A:T	H166Q	0.998
4:75491897:A:G	C148R	0.998
4:75491904:A:C	C145W	0.998
4:75491905:C:G	C145S	0.998
4:75491906:A:T	C145S	0.998
4:75494131:G:C	C125W	0.998
4:75494132:C:G	C125S	0.998
4:75494133:A:G	C125R	0.998
4:75494133:A:T	C125S	0.998
4:75494141:C:G	C122S	0.998
4:75494142:A:T	C122S	0.998
4:75494151:A:G	C119R	0.998
4:75508823:C:T	C108Y	0.998
4:75508824:A:G	C108R	0.998
4:75508832:C:G	C105S	0.998
4:75508833:A:T	C105S	0.998

dbSNP variants (sampled 300 via entrez): RS1000067470 (4:75503686 C>CA), RS1000096697 (4:75503989 G>T), RS1000234603 (4:75478554 G>A), RS1000253883 (4:75510787 A>C), RS1000365525 (4:75511059 A>G), RS1000429848 (4:75497565 C>T), RS1000587755 (4:75512164 T>C,G), RS1000702542 (4:75512427 A>G), RS1000741074 (4:75515690 T>G), RS1000833502 (4:75499531 A>G), RS1001052452 (4:75499836 G>A), RS1001151577 (4:75491101 GCTCT>G), RS1001252061 (4:75516597 A>C), RS1001282851 (4:75505722 C>G), RS1001443453 (4:75492350 A>G,T)

Disease associations

OMIM: gene MIM:607680 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (1): hypercholesterolemia, familial, 1 (MONDO:0007750)

Orphanet (1): Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001476_20	Response to tocilizumab in rheumatoid arthritis	9.000000e-07
GCST009391_401	Metabolite levels	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010386	phosphatidylcholine 38:4 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
sodium arsenite	affects expression, affects methylation, increases expression	3
Cadmium Chloride	increases abundance, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
quercitrin	decreases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
vanadyl sulfate	decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
fipronil	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression, increases degradation, increases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cadmium	increases abundance, increases expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
DEET	affects cotreatment, increases expression	1
Doxorubicin	decreases response to substance	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Mitoxantrone	affects response to substance	1
Phenobarbital	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	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_B2DK	Abcam HeLa RCHY1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT00005168	Not specified	COMPLETED	Hyperapo B and Coronary Heart Disease
NCT01753232	Not specified	COMPLETED	Safety and Efficacy of the DALI LDL-adsorber and MONET Lipoprotein Filter
NCT03018678	Not specified	COMPLETED	Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia
NCT03110432	Not specified	COMPLETED	Prospective German Very High Cardiovascular Risk Patients Dyslipidemia Treatment Indication Registry
NCT03795038	Not specified	COMPLETED	Comparison of the Plasma Lipoprotein Apheresis Systems DIAMED and MONET vs. the Whole Blood Apheresis System DALI
NCT03989167	Not specified	RECRUITING	Clinical Decision Support for Familial Hypercholesterolemia
NCT04073797	Not specified	RECRUITING	PET Imaging of Inflammation and Lipid Lowering Study
NCT04118348	Not specified	COMPLETED	Evaluating the Efficacy of Pediatric Lipid Screening Alerts
NCT04313270	Not specified	UNKNOWN	Subclinical Atherosclerosis in Patients With Familial Hypercholesterolemia Treated With Evolocumab®
NCT04526457	Not specified	COMPLETED	Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT04722068	Not specified	COMPLETED	Regeneron 1331 Kinetics Sub-Study HoFH
NCT04837638	Not specified	UNKNOWN	Diet Quality and Coronary Artery Calcification in Adults With Heterozygous Familial Hypercholesterolemia
NCT06555120	Not specified	RECRUITING	Screening for Familial Hypercholesterolemia in Children
NCT07543731	Not specified	NOT_YET_RECRUITING	A Real-World Study of Long-Term Adherence and Persistence to Inclisiran, Evolocumab, and Alirocumab