CHFR

Summary

CHFR (checkpoint with forkhead and ring finger domains, HGNC:20455) is a protein-coding gene on chromosome 12q24.33, encoding E3 ubiquitin-protein ligase CHFR (Q96EP1). E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons.

This gene encodes an E3 ubiquitin-protein ligase required for the maintenance of the antephase checkpoint that regulates cell cycle entry into mitosis and, therefore, may play a key role in cell cycle progression and tumorigenesis. The encoded protein has an N-terminal forkhead-associated domain, a central RING-finger domain, and a cysteine-rich C-terminal region. Alternatively spliced transcript variants that encode different protein isoforms have been described.

Source: NCBI Gene 55743 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 117 total — 1 likely-pathogenic
• MANE Select transcript: NM_001161346

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20455
Approved symbol	CHFR
Name	checkpoint with forkhead and ring finger domains
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10796, RNF196
Ensembl gene	ENSG00000072609
Ensembl biotype	protein_coding
OMIM	605209
Entrez	55743

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 58 protein_coding, 7 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000266880, ENST00000315585, ENST00000432561, ENST00000443047, ENST00000450056, ENST00000499045, ENST00000502279, ENST00000511001, ENST00000535181, ENST00000535527, ENST00000535897, ENST00000536196, ENST00000536843, ENST00000536932, ENST00000537551, ENST00000538235, ENST00000540537, ENST00000540963, ENST00000541341, ENST00000541817, ENST00000542714, ENST00000544093, ENST00000544268, ENST00000545046, ENST00000902527, ENST00000902528, ENST00000902529, ENST00000902530, ENST00000902531, ENST00000902532, ENST00000902533, ENST00000902534, ENST00000902535, ENST00000902536, ENST00000902537, ENST00000902538, ENST00000902539, ENST00000902540, ENST00000902541, ENST00000902542, ENST00000902543, ENST00000902544, ENST00000902545, ENST00000902546, ENST00000902547, ENST00000928594, ENST00000928595, ENST00000928596, ENST00000928597, ENST00000928598, ENST00000928599, ENST00000928600, ENST00000928601, ENST00000928602, ENST00000928603, ENST00000928604, ENST00000928605, ENST00000928606, ENST00000928607, ENST00000928608, ENST00000928609, ENST00000928610, ENST00000970962, ENST00000970963, ENST00000970964, ENST00000970965, ENST00000970966, ENST00000970967, ENST00000970968, ENST00000970969, ENST00000970970, ENST00000970971, ENST00000970972

RefSeq mRNA: 5 — MANE Select: NM_001161346 NM_001161344, NM_001161345, NM_001161346, NM_001161347, NM_018223

CCDS: CCDS31937, CCDS53847, CCDS53848, CCDS53849

Canonical transcript exons

ENST00000450056 — 18 exons

Exon	Start	End
ENSE00002226917	132887547	132887605
ENSE00002290836	132869619	132869798
ENSE00003466349	132861467	132861634
ENSE00003515405	132851618	132851737
ENSE00003527749	132887196	132887340
ENSE00003535580	132857405	132857559
ENSE00003542835	132848085	132848155
ENSE00003581591	132847043	132847130
ENSE00003581747	132843011	132843083
ENSE00003615486	132859068	132859227
ENSE00003617015	132856468	132856630
ENSE00003622509	132877555	132877654
ENSE00003627130	132844027	132844134
ENSE00003663138	132870724	132870783
ENSE00003663434	132872285	132872394
ENSE00003673123	132853431	132853573
ENSE00003721053	132848641	132848724
ENSE00003905913	132832356	132841596

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 94.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.4490 / max 966.8626, expressed in 1754 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134258	17.8145	1754
134262	6.6588	1679
134257	0.6137	364
134259	0.0089	3
134260	0.0079	3
134261	0.0039	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.24	gold quality
monocyte	CL:0000576	93.59	gold quality
mononuclear cell	CL:0000842	93.57	gold quality
leukocyte	CL:0000738	93.51	gold quality
skin of hip	UBERON:0001554	93.27	gold quality
sural nerve	UBERON:0015488	93.26	gold quality
blood	UBERON:0000178	93.23	gold quality
right testis	UBERON:0004534	92.27	gold quality
cortical plate	UBERON:0005343	92.21	gold quality
left testis	UBERON:0004533	92.14	gold quality
mucosa of stomach	UBERON:0001199	91.51	gold quality
upper lobe of left lung	UBERON:0008952	91.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.40	gold quality
lower esophagus	UBERON:0013473	91.39	gold quality
spleen	UBERON:0002106	91.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.21	gold quality
stromal cell of endometrium	CL:0002255	91.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.12	gold quality
upper lobe of lung	UBERON:0008948	91.01	gold quality
lower esophagus mucosa	UBERON:0035834	90.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.73	gold quality
thymus	UBERON:0002370	90.72	gold quality
esophagus	UBERON:0001043	90.65	gold quality
metanephros cortex	UBERON:0010533	90.65	gold quality
transverse colon	UBERON:0001157	90.49	gold quality
right lung	UBERON:0002167	90.47	gold quality
small intestine	UBERON:0002108	90.20	gold quality
adenohypophysis	UBERON:0002196	90.19	gold quality
esophagus mucosa	UBERON:0002469	90.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.10	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	480.45
E-GEOD-99795	no	56.23
E-ANND-3	no	4.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT1, HLTF, RELA

miRNA regulators (miRDB)

92 targeting CHFR, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3180-5P	99.82	69.12	2422

Literature-anchored findings (GeneRIF, showing 40)

• checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition (PMID:11807090)
• Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. (PMID:11912157)
• expression is downregulated by CpG island hypermethylation in esophageal cancer (PMID:12376479)
• Frequent hypermethylation of the 5’ CpG island of the mitotic stress checkpoint gene Chfr in colorectal and non-small cell lung cancer. (PMID:12538348)
• CHFR has a role in mitotic checkpoint control (PMID:12810945)
• Chfr may have a role in signaling the presence of mitotic stress induced by microtubule poisons (PMID:14562038)
• That the chfr gene is frequently silenced in various tumors because of methylation of its promoter, these findings suggest that chfr is inactivated by multiple mechanisms in human cancer. (PMID:14612512)
• Chfr is frequently inactivated in colon but not breast cancers, through a mechanism of hypermethylation of the promoter sequences. (PMID:14654793)
• Aberrant promoter methylation of the CHFR gene was observed in a significant proportion of human gastric cancers. (PMID:15201973)
• CHFR has a role in blocking mitosis along with p38 MAP kinase (PMID:15302856)
• PML bodies control the distribution, dynamics and function of CHFR (PMID:15467728)
• We conclude that the mechanism by which CHFR delays chromosome condensation involves inhibition of accumulation of Cyclin B1 in the nucleus. (PMID:15674323)
• The loss of checkpoint control associated with methylation of CHFR suggests the potential to overcome cell cycle checkpoints, which may lead to an accumulation of mutations. (PMID:15760919)
• downregulation of CHFR is a common event in nasopharyngeal carcinoma cells which may be due to hypermethylation of the gene promoter region (PMID:15937956)
• Results support the assertion that CHFR functions as an inhibitor of tumor proliferation. (PMID:16554732)
• CHFR might act as a tumor suppressor in at least some colorectal cancers and that CHFR methylation might, therefore, be a particular phenomenon of early colorectal cancer (PMID:17201143)
• Chfr activation by USP7 may play an important role in the regulation of Chfr-mediated cellular processes including cell cycle progression and tumor suppression. (PMID:17442268)
• CHFR has a role as a tumor suppressor in breast cancer (PMID:17596595)
• CHFR gene is neither mutated nor hypermethylated in ovarian cancer (PMID:17673375)
• Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes (PMID:17786301)
• Reveal for the first time that polymorphisms in the CHFR gene are associated with colorectal cancer susceptibility. (PMID:18079053)
• interaction of poly(ADP-ribose) with a PBZ motif in two representative human proteins, APLF (aprataxin PNK-like factor) and CHFR (checkpoint protein with FHA and RING domains) (PMID:18172500)
• confirmed that the FHA domain of CHFR plays an important role in initiating a cell cycle arrest at G2/M, indicating a functional link exists between the anti-proliferative effects and checkpoint function of this tumor suppressor protein via this domain (PMID:18335050)
• The Chfr-TCTP interaction was stable throughout the cell cycle, but it could be diminished by the complete depolymerization of the microtubules. (PMID:18504434)
• A novel role for CHFR regulating chromosome segregation where decreased expression, as seen in cancer cells, contributes to genomic instability by impairing the spindle assembly checkpoint. (PMID:18592005)
• results suggest the aberrant expression of Aurora-A and/or of CHFR contributed to the increase in the malignant potential of NSCLC, and that CHFR expression was impaired in smoking-related squamous cell carcinoma and might be a useful marker in NSCLC (PMID:18623126)
• Aberrant methylation of the CHFR gene may be involved in the carcinogenesis and development of gastric cancer, and is the predominant cause of down-regulation or loss of CHFR mRNA or protein expression (PMID:18763281)
• Chfr functions as a tumour suppressor by regulating HDAC1. (PMID:19182791)
• These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-kappaB. (PMID:19448676)
• Data show that the promoter methylation of CHFR was frequently accompanied with microsatellite instability, but not with clinicopathological factors in gastric cancer. (PMID:19469003)
• analysis of CHFR promoter hypermethylation and reduced CHFR mRNA expression in ovarian cancer (PMID:19634111)
• Aberrant promoter hypermethylation of the CHFR gene is associated with oral squamous cell carcinomas. (PMID:19787237)
• Gene methylation (CHFR, E-cadherin, BNIP3) in the peritoneal fluid could detect occult neoplastic cells in the peritoneum and might be a risk factor for peritoneal metastasis. (PMID:20082478)
• Aberrant methylation of the CHFR gene is a frequent event in the carcinogenesis of gastric cancer. (PMID:20109344)
• Aberrant promoter methylation of Runx3 and CHFR genes may be involved in the carcinogenesis and development of gastric cancer (PMID:20300977)
• this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer. (PMID:20388495)
• results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation (PMID:20473935)
• Taken together, their findings demonstrated that both epigenetic and genetic mechanisms were involved in silencing CHFR expression in EACs. (PMID:20564104)
• The PBZ motif of CHFR recognizes two adenine-containing subunits of PAR and the phosphate backbone that connects them (PMID:20880844)
• Hypermethylation of CHFR gene promoter is associated with loss or lower expression of CHFR mRNA in laryngeal squamous cell carcinoma. (PMID:20942233)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	chfr	ENSDARG00000075347
mus_musculus	Chfr	ENSMUSG00000014668
rattus_norvegicus	Chfr	ENSRNOG00000037430

Protein

Protein identifiers

E3 ubiquitin-protein ligase CHFR — Q96EP1 (reviewed: Q96EP1)

Alternative names: Checkpoint with forkhead and RING finger domains protein, RING finger protein 196, RING-type E3 ubiquitin transferase CHFR

All UniProt accessions (9): Q96EP1, A0A087WUN4, A0A087X0W6, A0A096P6K8, F5GWH4, F5H375, F5H5P5, F5H829, U3KPU9

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the ‘Lys-48’-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of ‘Lys-63’-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at ‘Lys-63’ are usually not targeted for degradation, but are rather involved in signaling cellular stress.

Subunit / interactions. Interacts with HDAC1 and HDAC2. Interacts with PML (with sumoylated form of PML).

Subcellular location. Nucleus. PML body.

Tissue specificity. Ubiquitous.

Post-translational modifications. Poly-ADP-ribosylated. In addition to binding non covalently poly(ADP-ribose) via its PBZ-type zinc finger, the protein is also covalently poly-ADP-ribosylated by PARP1. Autoubiquitinated; may regulate its cellular level. Phosphorylated by PKB. Phosphorylation may affect its E3 ligase activity.

Domain organisation. The PBZ-type zinc finger (also named CYR) mediates non-covalent poly(ADP-ribose)-binding. Poly(ADP-ribose)-binding is dependent on the presence of zinc and is required for its function in antephase checkpoint. The FHA domain plays a key role in the anti-proliferative properties of the protein and is involved in initiating a cell cycle arrest at G2/M. The FHA domain may be required to interact with phosphorylated proteins.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. CHFR is silenced in many primary cancers because of CpG methylation and deacetylated histones on its promoter region. This however raises the question of whether CHFR silencing is a consequence or a cause of primary cancers.

Similarity. Belongs to the CHFR family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96EP1-1	1	yes
Q96EP1-2	2
Q96EP1-3	3
Q96EP1-4	4
Q96EP1-5	5

RefSeq proteins (5): NP_001154816, NP_001154817, NP_001154818, NP_001154819, NP_060693 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR001841	Znf_RING	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR040909	CHFR_Znf-CRD	Domain
IPR052256	E3_ubiquitin-ligase_CHFR	Family

Pfam: PF00498, PF13923, PF17979

UniProt features (69 total): strand 16, helix 13, mutagenesis site 9, sequence variant 6, splice variant 4, sequence conflict 4, region of interest 4, turn 4, compositionally biased region 3, modified residue 2, zinc finger region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2XOC	X-RAY DIFFRACTION	1.89
2XP0	X-RAY DIFFRACTION	1.98
1LGP	X-RAY DIFFRACTION	2
1LGQ	X-RAY DIFFRACTION	2.1
2XOZ	X-RAY DIFFRACTION	2.37
2XOY	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EP1-F1	73.22	0.50

Functional residue map

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

Post-translational modifications (2): 244, 386

Mutagenesis-validated functional residues (9):

Position	Phenotype
39	abolishes phosphorylation but not autoubiquitination; when associated with a-205.
205	abolishes phosphorylation but not autoubiquitination; when associated with a-39.
306	abolishes autoubiquitination. does not affect phosphorylation.
332	abolishes autoubiquitination in vitro.
632	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1.
635	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-641.
641	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-635.
642	impairs poly(adp-ribose)-binding and poly-adp-ribosylation by parp1.
644	impairs poly(adp-ribose)-binding and poly-adp-ribosylation by parp1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 243 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GOBP_CHROMOSOME_SEPARATION, GOBP_REGULATION_OF_MEIOTIC_CELL_CYCLE, CAGCTG_AP4_Q5, YY1_Q6, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT

GO Biological Process (10): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), positive regulation of protein ubiquitination (GO:0031398), protein destabilization (GO:0031648), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), meiotic spindle checkpoint signaling (GO:0044779), mitotic G2/M transition checkpoint (GO:0044818), cell division (GO:0051301), mitotic cell cycle (GO:0000278), protein ubiquitination (GO:0016567)

GO Molecular Function (7): nucleotide binding (GO:0000166), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), PML body (GO:0016605)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
modification-dependent protein catabolic process	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of protein stability	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
spindle checkpoint signaling	1
meiotic cell cycle checkpoint signaling	1
meiotic cell cycle	1
negative regulation of metaphase/anaphase transition of meiotic cell cycle	1
mitotic cell cycle checkpoint signaling	1
negative regulation of G2/M transition of mitotic cell cycle	1
cellular process	1
cell cycle	1
mitotic nuclear division	1
protein modification by small protein conjugation	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear body	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHFR	APLF	Q8IW19	979
CHFR	APTX	Q7Z2E3	831
CHFR	XRCC1	P18887	770
CHFR	LIG3	P49916	756
CHFR	XRCC4	Q13426	631
CHFR	RASSF1	Q9NS23	605
CHFR	MGMT	P16455	582
CHFR	UBE2N	P61088	574
CHFR	RNF146	Q9NTX7	565
CHFR	KIF22	Q14807	555
CHFR	HDAC1	Q13547	548
CHFR	MLH1	P40692	545
CHFR	DAPK1	P53355	540
CHFR	CDH13	P55290	522
CHFR	TPT1	P13693	520

IntAct

31 interactions, top by confidence:

A	B	Type	Score
C5orf24	MEIS1	psi-mi:“MI:0914”(association)	0.530
DTX3	ITSN1	psi-mi:“MI:0914”(association)	0.530
UBE2D1	CHFR	psi-mi:“MI:0915”(physical association)	0.490
UBE2D2	CHFR	psi-mi:“MI:0915”(physical association)	0.490
CHFR	UBE2N	psi-mi:“MI:0915”(physical association)	0.490
CHFR	UBE2D4	psi-mi:“MI:0915”(physical association)	0.490
CHFR	UBE2W	psi-mi:“MI:0915”(physical association)	0.490
CHFR	TPT1	psi-mi:“MI:0915”(physical association)	0.370
TPT1	CHFR	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	CHFR	psi-mi:“MI:0915”(physical association)	0.370
UBE2E1	CHFR	psi-mi:“MI:0915”(physical association)	0.370
UBE2E2	CHFR	psi-mi:“MI:0915”(physical association)	0.370
CHFR	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
RNF7	CHFR	psi-mi:“MI:0915”(physical association)	0.370
CHFR	CBLC	psi-mi:“MI:0915”(physical association)	0.370
CHFR	RNF125	psi-mi:“MI:0915”(physical association)	0.370
CHFR	TRIM9	psi-mi:“MI:0915”(physical association)	0.370
PARP1	KPNA3	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
DTX3	EIF3F	psi-mi:“MI:0914”(association)	0.350
CHFR	EEF1G	psi-mi:“MI:0915”(physical association)	0.000
BRD4	CHFR	psi-mi:“MI:0915”(physical association)	0.000
CHFR	GABBR1	psi-mi:“MI:0915”(physical association)	0.000
CHFR	ITGAE	psi-mi:“MI:0915”(physical association)	0.000
CHFR	WDR47	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (115): RANBP2 (Affinity Capture-MS), USP7 (Affinity Capture-MS), HLTF (Affinity Capture-MS), PARP1 (Affinity Capture-MS), MCM2 (Affinity Capture-MS), HDAC1 (Affinity Capture-MS), CDC20 (Affinity Capture-MS), VIM (Affinity Capture-MS), AURKA (Affinity Capture-MS), CDK5 (Affinity Capture-MS), PCNA (Affinity Capture-MS), USP7 (Affinity Capture-Western), AURKA (Affinity Capture-Western), PLK1 (Affinity Capture-Western), HDAC2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1L8GLK3, A0A974CYQ5, A2AHJ4, A5WW08, D2HNY3, D2HWM5, E7F6T8, F1ND48, O15040, O70260, O95071, P59328, Q3TLR7, Q4V837, Q58DC2, Q58WW2, Q5E9J6, Q5F479, Q5FWP4, Q5NVC7, Q5R9B8, Q5RF77, Q5RGA4, Q5RHI5, Q5ZLG9, Q62671, Q66JG1, Q6DDH2, Q6P1W0, Q6P256, Q6PCD5, Q6PJI9, Q6RI45, Q80TP3, Q80U93, Q810L3, Q8C0M0, Q8CBW4, Q8CIK8, Q8CIN9

Diamond homologs: A5WW08, O75382, P29128, P29836, Q54BF0, Q5FWP4, Q5RBG2, Q5RF77, Q5RKG6, Q6P256, Q6PJ69, Q810L3, Q8C006, Q96EP1, Q9UPQ4, A0A7I2V3R4, A4IF63, A5D7F8, A5D8S5, D2GXS7, D3ZQG6, F7H9X2, O70277, P21333, P29590, Q03601, Q28E95, Q5RBR0, Q69ZI1, Q6FPI4, Q6NRD3, Q71F54, Q75EN0, Q7Z6J0, Q80X90, Q8BTM8, Q8C120, Q8IWR1, Q8NG06, Q8TEJ3

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	CHFR	ubiquitination
CHFR	“down-regulates quantity by destabilization”	HLTF	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	CHFR	ubiquitination
USP7	“up-regulates quantity by stabilization”	CHFR	deubiquitination
CHFR	“down-regulates quantity by destabilization”	AURKA	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	PLK1	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	HDAC1	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	KIF22	ubiquitination
CHFR	“down-regulates quantity by destabilization”	PARP1	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	PBK	polyubiquitination
CHFR	“down-regulates quantity”	SIRT1	ubiquitination
CHFR	“down-regulates quantity by destabilization”	SMARCA4	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	SMARCB1	polyubiquitination
CHFR	“down-regulates quantity by destabilization”	SMARCD1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	76.8×	3e-07
E3 ubiquitin ligases ubiquitinate target proteins	5	40.3×	3e-06
Antigen processing: Ubiquitination & Proteasome degradation	11	17.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	6	87.1×	1e-08
protein monoubiquitination	6	76.4×	1e-08
protein K48-linked ubiquitination	7	43.7×	1e-08
protein polyubiquitination	7	29.9×	1e-07
ubiquitin-dependent protein catabolic process	8	22.0×	9e-08
protein ubiquitination	9	13.8×	3e-07
proteasome-mediated ubiquitin-dependent protein catabolic process	6	11.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	89
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1802254	NM_001161346.2(CHFR):c.1231C>T (p.Gln411Ter)	Likely pathogenic

SpliceAI

4995 predictions. Top by Δscore:

Variant	Effect	Δscore
12:132844022:CTTA:C	donor_loss	1.0000
12:132844023:TTAC:T	donor_loss	1.0000
12:132844024:TACC:T	donor_loss	1.0000
12:132844025:A:AC	donor_gain	1.0000
12:132844026:C:CA	donor_loss	1.0000
12:132844026:C:CC	donor_gain	1.0000
12:132844026:CCTGG:C	donor_gain	1.0000
12:132844131:TAAT:T	acceptor_gain	1.0000
12:132844132:AAT:A	acceptor_gain	1.0000
12:132844133:AT:A	acceptor_gain	1.0000
12:132844135:C:CC	acceptor_gain	1.0000
12:132847037:ACTCA:A	donor_loss	1.0000
12:132847039:TCACC:T	donor_loss	1.0000
12:132847042:C:CA	donor_loss	1.0000
12:132847042:CCAGA:C	donor_gain	1.0000
12:132847126:TAATT:T	acceptor_gain	1.0000
12:132847127:AATT:A	acceptor_gain	1.0000
12:132847128:ATT:A	acceptor_gain	1.0000
12:132847129:TT:T	acceptor_gain	1.0000
12:132847129:TTC:T	acceptor_loss	1.0000
12:132847130:TCT:T	acceptor_loss	1.0000
12:132847131:C:A	acceptor_loss	1.0000
12:132847131:C:CC	acceptor_gain	1.0000
12:132847132:T:A	acceptor_loss	1.0000
12:132847133:G:C	acceptor_gain	1.0000
12:132847137:C:CT	acceptor_gain	1.0000
12:132847139:C:CT	acceptor_gain	1.0000
12:132847140:A:T	acceptor_gain	1.0000
12:132848079:CGGTA:C	donor_loss	1.0000
12:132848080:GGTAC:G	donor_loss	1.0000

AlphaMissense

4234 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:132841584:A:C	H655Q	1.000
12:132841584:A:T	H655Q	1.000
12:132843040:G:C	C641W	1.000
12:132843041:C:A	C641F	1.000
12:132843041:C:G	C641S	1.000
12:132843041:C:T	C641Y	1.000
12:132843042:A:G	C641R	1.000
12:132843042:A:T	C641S	1.000
12:132843050:C:A	G638V	1.000
12:132843050:C:T	G638D	1.000
12:132843051:C:A	G638C	1.000
12:132843051:C:G	G638R	1.000
12:132843058:G:C	C635W	1.000
12:132843059:C:G	C635S	1.000
12:132843059:C:T	C635Y	1.000
12:132843060:A:G	C635R	1.000
12:132843060:A:T	C635S	1.000
12:132857492:A:G	C339R	1.000
12:132857513:A:G	W332R	1.000
12:132857513:A:T	W332R	1.000
12:132857534:A:G	C325R	1.000
12:132859105:A:G	C304R	1.000
12:132841586:G:C	H655D	0.999
12:132841591:A:G	F653S	0.999
12:132843016:G:C	H649Q	0.999
12:132843016:G:T	H649Q	0.999
12:132843018:G:C	H649D	0.999
12:132843018:G:T	H649N	0.999
12:132843052:C:A	W637C	0.999
12:132843052:C:G	W637C	0.999

dbSNP variants (sampled 300 via entrez): RS1000037919 (12:132835163 G>A,C), RS1000110400 (12:132863599 C>T), RS1000151857 (12:132875516 G>A), RS1000192109 (12:132838437 C>A), RS1000242998 (12:132872721 C>T), RS1000247539 (12:132878500 T>C), RS1000300479 (12:132887329 CG>C), RS1000304816 (12:132860484 T>C), RS1000333841 (12:132860737 A>G), RS1000389331 (12:132838692 C>A,T), RS1000527346 (12:132889333 G>A), RS1000559531 (12:132856634 G>A,C), RS1000629403 (12:132855438 C>G,T), RS1000659512 (12:132853587 C>A,T), RS1000663880 (12:132843851 A>C)

Disease associations

OMIM: gene MIM:605209 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002386_20	Cognitive function	2.000000e-06
GCST007327_120	Smoking status (ever vs never smokers)	3.000000e-09
GCST008810_7	Smoking initiation (ever regular vs never regular)	4.000000e-08
GCST008839_182	Height	5.000000e-11
GCST010002_179	Refractive error	1.000000e-12
GCST010252_3	Systolic blood pressure x quantitative lifestyle risk score interaction (2df test)	4.000000e-06
GCST010253_1	Systolic blood pressure x quantitative lifestyle risk score interaction (1df test)	8.000000e-07
GCST90002390_182	Mean corpuscular hemoglobin	6.000000e-11
GCST90002392_403	Mean corpuscular volume	7.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0003925	cognition
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0006335	systolic blood pressure
EFO:0010724	lifestyle measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases methylation	2
Arsenic	decreases expression, increases abundance, affects methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	increases expression	1
beta-methylcholine	affects expression	1
abrine	increases expression	1
Bortezomib	decreases expression	1
Erlotinib Hydrochloride	affects response to substance, affects cotreatment	1
Docetaxel	affects response to substance, decreases response to substance	1
Resveratrol	increases expression, affects cotreatment	1
Temozolomide	increases expression	1
Decitabine	increases expression	1
Acetaminophen	affects response to substance	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	affects cotreatment, affects response to substance	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Polychlorinated Biphenyls	affects expression	1
Smoke	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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