GEN1

Summary

GEN1 (GEN1 structure-specific endonuclease, HGNC:26881) is a protein-coding gene on chromosome 2p24.2, encoding Flap endonuclease GEN homolog 1 (Q17RS7). Endonuclease which resolves Holliday junctions (HJs) by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated.

This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 348654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary breast carcinoma (Refuted, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,498 total
• Dosage sensitivity (ClinGen): haploinsufficiency dosage sensitivity unlikely, triplosensitivity no evidence
• MANE Select transcript: NM_001130009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26881
Approved symbol	GEN1
Name	GEN1 structure-specific endonuclease
Location	2p24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ40869, Gen
Ensembl gene	ENSG00000178295
Ensembl biotype	protein_coding
OMIM	612449
Entrez	348654

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000317402, ENST00000381254, ENST00000524465, ENST00000528873, ENST00000532257, ENST00000534451, ENST00000534669, ENST00000614478, ENST00000862145, ENST00000862146, ENST00000862147, ENST00000862148, ENST00000912259, ENST00000912260, ENST00000912261, ENST00000912262

RefSeq mRNA: 2 — MANE Select: NM_001130009 NM_001130009, NM_182625

CCDS: CCDS1691

Canonical transcript exons

ENST00000381254 — 14 exons

Exon	Start	End
ENSE00001487977	17780621	17788946
ENSE00003480502	17773096	17773132
ENSE00003585520	17761396	17761582
ENSE00003683718	17773219	17773299
ENSE00003726073	17771196	17771287
ENSE00003729561	17772634	17772784
ENSE00003743219	17778002	17778063
ENSE00003743591	17779978	17780121
ENSE00003744092	17774271	17774401
ENSE00003843242	17754138	17754345
ENSE00003888719	17759929	17760104
ENSE00003891383	17764897	17765073
ENSE00003892667	17768738	17768811
ENSE00003893538	17766579	17766689

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 89.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6205 / max 142.3994, expressed in 1670 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19092	6.1556	1290
19089	1.3153	954
19090	1.0948	769
19091	0.0547	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.39	gold quality
bone marrow cell	CL:0002092	87.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.27	gold quality
endothelial cell	CL:0000115	85.13	gold quality
epithelium of nasopharynx	UBERON:0001951	84.54	gold quality
ventricular zone	UBERON:0003053	83.96	gold quality
pancreatic ductal cell	CL:0002079	83.64	gold quality
adrenal tissue	UBERON:0018303	83.36	gold quality
epithelial cell of pancreas	CL:0000083	82.44	gold quality
tonsil	UBERON:0002372	81.59	gold quality
vermiform appendix	UBERON:0001154	81.54	gold quality
rectum	UBERON:0001052	81.38	gold quality
right uterine tube	UBERON:0001302	79.53	gold quality
right testis	UBERON:0004534	79.50	gold quality
testis	UBERON:0000473	79.37	gold quality
ganglionic eminence	UBERON:0004023	79.05	gold quality
left testis	UBERON:0004533	79.04	gold quality
right lobe of liver	UBERON:0001114	78.54	gold quality
minor salivary gland	UBERON:0001830	78.48	gold quality
lymph node	UBERON:0000029	77.92	gold quality
bone marrow	UBERON:0002371	77.62	gold quality
esophagus mucosa	UBERON:0002469	77.59	gold quality
pigmented layer of retina	UBERON:0001782	77.47	gold quality
sperm	CL:0000019	77.43	gold quality
gall bladder	UBERON:0002110	77.15	gold quality
stromal cell of endometrium	CL:0002255	77.09	gold quality
caecum	UBERON:0001153	76.90	gold quality
mouth mucosa	UBERON:0003729	76.52	gold quality
transverse colon	UBERON:0001157	76.16	gold quality
colonic epithelium	UBERON:0000397	75.39	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	8.59
E-ANND-3	yes	5.02
E-CURD-10	no	340.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting GEN1, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893

Functional genomics

ClinGen dosage: haploinsufficiency 40 (dosage sensitivity unlikely), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• Recombinant GEN1 and Yen1 resolve Holliday junctions by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated (PMID:19020614)
• ectopic expression of GEN1 in fission yeast mus81Delta strains results in Holliday junction resolution and crossover formation during meiosis. (PMID:20040574)
• Data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene. (PMID:20512659)
• Study shows that, like E coli Holliday junction (HJ)resolvase RuvC, GEN1 binds specifically to HJs and resolves them by a dual incision mechanism in which nicks are introduced in the pair of continuous strands within the lifetime of the GEN1-HJ complex. (PMID:20634321)
• Study observed centrosome defects in the absence of XRCC3. While RAD51B and RAD51C act early in homologous recombination, XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution. (PMID:23108668)
• Our findings provide novel insight into the biological functions of GEN1 by uncovering an important role of GEN1 in the regulation of centrosome integrity. (PMID:23166748)
• Data show that three structure-selective endonucleases, SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of Holliday junctions (HJs) resolution in HeLa cells. (PMID:24076221)
• GEN1 activity cannot be substituted for the SLX4-associated nucleases, and one of the HJ resolvase activities, either of those associated with SLX4 or with GEN1, is required for cell viability, even in the presence of BLM. (PMID:24080495)
• GEN1 is controlled by nuclear exclusion, driven by a nuclear export signal that restricts GEN1 actions to mitosis. Spatial control of GEN1 contributes to genome stability by avoiding competition with non-crossover promoting repair pathways. (PMID:25209024)
• human GEN1 protein promotes Holliday junction resolution by a mechanism that is analogous to that exhibited by the prototypic HJ resolvase E. coli RuvC. (PMID:26578604)
• Data suggest that dimeric GEN1 binds with high affinity/selectivity to Holliday junctions, introducing two symmetrical hydrolytic cleavages of phosphodiester backbone; at present, less is known about SLX1-SLX4-MUS81-EME1 resolving enzyme complex. (GEN1 = Holliday junction 5’ flap endonuclease; SLX = structure-specific endonuclease subunit; MUS81 = MUS81 endonuclease; EME1 = essential meiotic endonuclease 1) [REVIEW] (PMID:27990631)
• GEN1 efficiently cleaves both single and double Holliday junctions contained within large recombination intermediates. Moreover, we find that GEN1 exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA. (PMID:28049850)
• Using RNAi or FA-P cells complemented with SLX4 mutants that abrogate interaction with MUS81 or SLX1, we show that SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised forks by GEN1. (PMID:28290553)
• the in vitro activities of DmGen and HsGEN1 are strikingly similar. (PMID:28369583)
• The tight binding of GEN1 monomer to intact- and singly-cleaved Holliday junctions empowers it as the last resort to process Holliday junctions that escape the primary mechanisms (PMID:30590761)
• NCAPH Stabilizes GEN1 in Chromatin to Resolve Ultra-Fine DNA Bridges and Maintain Chromosome Stability. (PMID:36380731)
• Reverse Transcription-PCR-based Sanger Sequencing-confirmed Exon-skipping Effect of a Novel GEN1 Intronic Variant (c.1408+4A>G). (PMID:37840312)
• GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract. (PMID:38654324)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000112451
mus_musculus	Gen1	ENSMUSG00000051235
rattus_norvegicus	Gen1	ENSRNOG00000004667
drosophila_melanogaster	Gen	FBGN0263831

Paralogs (2): FEN1 (ENSG00000168496), EXO1 (ENSG00000174371)

Protein

Protein identifiers

Flap endonuclease GEN homolog 1 — Q17RS7 (reviewed: Q17RS7)

All UniProt accessions (4): Q17RS7, A0A087WXY3, E9PLG0, E9PM30

UniProt curated annotations — full annotation on UniProt →

Function. Endonuclease which resolves Holliday junctions (HJs) by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated. Four-way DNA intermediates, also known as Holliday junctions, are formed during homologous recombination and DNA repair, and their resolution is necessary for proper chromosome segregation. Cleaves HJs by a nick and counter-nick mechanism involving dual coordinated incisions that lead to the formation of ligatable nicked duplex products. Cleavage of the first strand is rate limiting, while second strand cleavage is rapid. Largely monomeric, dimerizes on the HJ and the first nick occurs upon dimerization at the junction. Efficiently cleaves both single and double HJs contained within large recombination intermediates. Exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA. Also has endonuclease activity on 5’-flap and replication fork (RF) DNA substrates.

Subunit / interactions. Largely monomeric, dimerizes on the Holliday junction and the first nick occurs upon dimerization at the junction.

Subcellular location. Nucleus.

Cofactor. Binds 2 magnesium ions per subunit. They probably participate in the reaction catalyzed by the enzyme. May bind an additional third magnesium ion after substrate binding.

Domain organisation. XPG-N, XPG-I,5’-3’ exonuclease domains interact with DNA. Contains a chromodomain that acts as additional DNA interaction site and is required for efficient DNA recognition and cleavage.

Similarity. Belongs to the XPG/RAD2 endonuclease family. GEN subfamily.

RefSeq proteins (2): NP_001123481, NP_872431 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006084	XPG/Rad2	Family
IPR006085	XPG_DNA_repair_N	Domain
IPR006086	XPG-I_dom	Domain
IPR008918	HhH2	Conserved_site
IPR029060	PIN-like_dom_sf	Homologous_superfamily
IPR036279	5-3_exonuclease_C_sf	Homologous_superfamily
IPR041012	GEN_chromo	Domain

Pfam: PF00752, PF00867, PF18704

Enzyme classification (BRENDA):

• EC 3.1.21.10 — crossover junction endodeoxyribonuclease (BRENDA: 47 organisms, 156 substrates, 9 inhibitors, 10 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
3’-FLAPPED JUNCTION IN DNA	—	2
DNA JUNCTION 1	0.0001	2
D-LOOP JUNCTION IN DNA	—	1
INTACT HOLLIDAY JUNCTION	—	1
NXO12 JUNCTION IN SINGLE-STRANDED DNA	—	1
PXO12-3’ JUNCTION IN SINGLE-STRANDED DNA	—	1
REPLICATION FORK-LIKE JUNCTION IN DNA	—	1
SPLAYED Y JUNCTION IN DNA	—	1
DNA JUNCTION 1 UNCONSTRAINED	—	0
DNA JUNCTION J1T1	—	0
DNA JUNCTION J1T2	—	0
DNA JUNCTION RC1	—	0
DNA JUNCTION RC1(1,3')	—	0
DNA JUNCTION RC1(2,3')	—	0
HOLLIDAY JUNCTION 3 IN DNA	—	0

UniProt features (65 total): helix 17, mutagenesis site 12, strand 11, sequence variant 8, binding site 7, region of interest 4, turn 3, modified residue 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5T9J	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q17RS7-F1	61.79	0.29

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 (7): 157; 208; 30; 75; 134; 136; 155

Post-translational modifications (2): 801, 802

Mutagenesis-validated functional residues (12):

Position	Phenotype
30	abolishes endonuclease activity on both hollyday junctions and 5’ flap substrates.
36	abolishes endonuclease activity on both hollyday junctions and 5’ flap substrates.
54	reduces by 50% endonuclease activity on both hollyday junctions and 5’ flap substrates.
89	no effect on endonuclease activity on hollyday junctions. slightly reduces endonuclease activity on 5’ flap substrates.
93	no effect on endonuclease activity on hollyday junctions. slightly reduces endonuclease activity on 5’ flap substrates.
109	strongly reduces endonuclease activity on both hollyday junctions and 5’ flap substrates.
110	reduces by 25% endonuclease activity on hollyday junctions and by 65% on 5’ flap substrates.
134–136	abolishes endonuclease activity.
380	no effect on endonuclease activity on both hollyday junctions and 5’ flap substrates.
404	no effect on endonuclease activity on both hollyday junctions and 5’ flap substrates.
406	no effect on endonuclease activity on both hollyday junctions and 5’ flap substrates.
438	no effect on endonuclease activity on both hollyday junctions and 5’ flap substrates.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates

MSigDB gene sets: 247 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOMF_ENDONUCLEASE_ACTIVITY, WANG_CLIM2_TARGETS_UP, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOMF_NUCLEASE_ACTIVITY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_CHROMOSOME_SEPARATION

GO Biological Process (9): double-strand break repair via homologous recombination (GO:0000724), regulation of centrosome duplication (GO:0010824), replication fork processing (GO:0031297), resolution of DNA recombination intermediates (GO:0071139), resolution of mitotic recombination intermediates (GO:0071140), positive regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090267), DNA repair (GO:0006281), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (12): magnesium ion binding (GO:0000287), four-way junction DNA binding (GO:0000400), crossover junction DNA endonuclease activity (GO:0008821), 5’-flap endonuclease activity (GO:0017108), protein homodimerization activity (GO:0042803), DNA binding (GO:0003677), catalytic activity (GO:0003824), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), centrosome (GO:0005813), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Resolution of D-Loop Structures	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	3
recombinational repair	1
double-strand break repair	1
regulation of centrosome cycle	1
centrosome duplication	1
DNA-templated DNA replication maintenance of fidelity	1
DNA recombination	1
mitotic recombination	1
resolution of DNA recombination intermediates	1
mitotic spindle assembly checkpoint signaling	1
positive regulation of cell cycle process	1
positive regulation of spindle checkpoint	1
regulation of mitotic cell cycle spindle assembly checkpoint	1
DNA damage response	1
cellular response to stress	1
metal ion binding	1
DNA secondary structure binding	1
DNA endonuclease activity, producing 3’-phosphomonoesters	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
flap endonuclease activity	1
identical protein binding	1
protein dimerization activity	1
nucleic acid binding	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
endonuclease activity	1
DNA nuclease activity	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
centriole	1
microtubule organizing center	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2310 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GEN1	EME1	Q96AY2	863
GEN1	MUS81	Q96NY9	861
GEN1	SLX4	Q8IY92	834
GEN1	SLX1A	Q9BQ83	816
GEN1	RMI1	Q9H9A7	796
GEN1	RMI2	Q96E14	762
GEN1	DNA2	P51530	756
GEN1	TOP3A	Q13472	675
GEN1	FANCM	Q8IYD8	665
GEN1	WRN	Q14191	623
GEN1	RAD51	Q06609	609
GEN1	RAD52	P43351	602
GEN1	BRCA2	P51587	591
GEN1	SMC6	Q96SB8	563
GEN1	MRE11	P49959	562

IntAct

11 interactions, top by confidence:

A	B	Type	Score
PLOD3	COL4A1	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
TNFRSF1B	MAP3K7	psi-mi:“MI:0914”(association)	0.350
ODF2	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CEP135	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
KRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270
U2AF2	NACA	psi-mi:“MI:2364”(proximity)	0.270
HUNK	GEN1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): GEN1 (Affinity Capture-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Synthetic Lethality), GEN1 (Affinity Capture-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Proximity Label-MS), GEN1 (Affinity Capture-MS), GEN1 (Affinity Capture-MS), GEN1 (Affinity Capture-MS), GEN1 (Proximity Label-MS)

ESM2 similar proteins: A0A3Q2TTB3, A0JMR6, A4IIA7, F4JNY0, F6RRD7, I3XHK1, O60934, O88622, P14629, P28715, P79457, Q08DZ8, Q12789, Q17RS7, Q1LWH4, Q28I29, Q32PL8, Q3B7T1, Q4R7Q1, Q5FWP4, Q5M954, Q5QJC2, Q5RA37, Q5RCV3, Q5ZIN2, Q66J91, Q6GQV7, Q6NVF4, Q6P1E7, Q6P1H6, Q6P256, Q6P7W5, Q76CY8, Q7TP65, Q86W56, Q8BMI4, Q8C0W1, Q8C5W4, Q8GT06, Q8IXW5

Diamond homologs: A0B9M7, A1RSC7, A1RWY2, A3CWV2, A3DMG2, A3FPN7, A3MY15, A4HFE4, A4I2L4, A4S1G4, A4WNC4, A5KAL1, A5UL52, A6UX46, A7AX58, A7IA59, A7RRJ0, A8AAC1, A8B672, A8M9L3, A8NQC2, B0E412, B0EN90, B0UXL7, B1YC46, B3MDA3, B3NP61, B4GIM3, B4HTA1, B4J6M4, B4LM90, B4MR84, B4P5U9, B4QIG6, B5DUR8, B6AFP1, B6JYI7, B7XHS8, B8C6S5, B8GIA0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DCAF11	“down-regulates quantity by destabilization”	GEN1	binding
Cullin4-RBX1-DDB1	“down-regulates quantity by destabilization”	GEN1	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1498 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1003
Likely benign	399
Benign	61

Top pathogenic / likely-pathogenic (0)

SpliceAI

2743 predictions. Top by Δscore:

Variant	Effect	Δscore
2:17761551:G:GT	donor_gain	1.0000
2:17761578:GAGAG:G	donor_gain	1.0000
2:17761580:GAGG:G	donor_loss	1.0000
2:17761581:AG:A	donor_loss	1.0000
2:17761582:GGTG:G	donor_loss	1.0000
2:17761584:T:A	donor_loss	1.0000
2:17764895:A:AG	acceptor_gain	1.0000
2:17764896:G:GG	acceptor_gain	1.0000
2:17765052:G:GT	donor_gain	1.0000
2:17765053:A:T	donor_gain	1.0000
2:17765070:AAAG:A	donor_loss	1.0000
2:17765071:AAGG:A	donor_loss	1.0000
2:17765072:AGG:A	donor_loss	1.0000
2:17765073:GG:G	donor_loss	1.0000
2:17765074:G:C	donor_loss	1.0000
2:17765075:T:A	donor_loss	1.0000
2:17766576:TAG:T	acceptor_loss	1.0000
2:17766577:A:AG	acceptor_gain	1.0000
2:17766577:AG:A	acceptor_gain	1.0000
2:17766577:AGGAC:A	acceptor_loss	1.0000
2:17766578:G:A	acceptor_gain	1.0000
2:17766578:G:GG	acceptor_gain	1.0000
2:17766578:GGA:G	acceptor_gain	1.0000
2:17766578:GGAC:G	acceptor_gain	1.0000
2:17766578:GGACC:G	acceptor_gain	1.0000
2:17766688:AGGTA:A	donor_loss	1.0000
2:17766689:GGT:G	donor_loss	1.0000
2:17766690:G:GG	donor_gain	1.0000
2:17766690:GTAAG:G	donor_loss	1.0000
2:17766691:T:G	donor_loss	1.0000

AlphaMissense

6030 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:17778051:T:A	W418R	0.998
2:17778051:T:C	W418R	0.998
2:17760043:T:A	W34R	0.997
2:17760043:T:C	W34R	0.997
2:17774295:T:A	W366R	0.996
2:17774295:T:C	W366R	0.996
2:17778053:G:C	W418C	0.996
2:17778053:G:T	W418C	0.996
2:17761480:A:C	K82N	0.995
2:17761480:A:T	K82N	0.995
2:17759962:T:A	W7R	0.993
2:17759962:T:C	W7R	0.993
2:17778052:G:C	W418S	0.993
2:17760026:C:A	A28E	0.992
2:17760029:T:A	V29D	0.992
2:17760037:A:C	S32R	0.992
2:17760039:T:A	S32R	0.992
2:17760039:T:G	S32R	0.992
2:17761452:T:A	V73D	0.992
2:17765045:T:A	V166D	0.992
2:17771266:T:C	C261R	0.992
2:17773231:T:C	F335L	0.992
2:17773233:C:A	F335L	0.992
2:17773233:C:G	F335L	0.992
2:17760101:T:C	L53P	0.991
2:17761409:C:A	R59S	0.991
2:17761410:G:C	R59P	0.991
2:17768742:T:A	V214D	0.991
2:17774297:G:C	W366C	0.991
2:17774297:G:T	W366C	0.991

dbSNP variants (sampled 300 via entrez): RS1000085748 (2:17756356 G>A,T), RS1000140328 (2:17786649 T>G), RS1000169985 (2:17778681 C>T), RS1000175310 (2:17782348 G>A), RS1000226013 (2:17782743 G>A), RS1000369054 (2:17767347 A>G), RS1000563116 (2:17752859 T>C), RS1000589798 (2:17775106 A>G), RS1000739259 (2:17787721 C>T), RS1000760787 (2:17762127 CTT>C), RS1000802184 (2:17767109 G>A,T), RS1000854661 (2:17762378 GT>G,GTT), RS1000935256 (2:17752508 A>G), RS1000981463 (2:17764756 C>A,T), RS1001019378 (2:17757931 T>C)

Disease associations

OMIM: gene MIM:612449 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
familial ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hereditary breast carcinoma	Refuted	AD
familial ovarian cancer	No Known Disease Relationship	AD

Mondo (3): hereditary neoplastic syndrome (MONDO:0015356), breast neoplasm (MONDO:0021100), familial ovarian cancer (MONDO:0016248)

Orphanet (1): Inherited cancer-predisposing syndrome (Orphanet:140162)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

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
Cisplatin	decreases expression, decreases response to substance, increases expression	2
Methyl Methanesulfonate	increases expression	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression	1
avobenzone	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
azoxystrobin	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	decreases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	increases methylation	1
Benzo(a)pyrene	increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Endosulfan	decreases expression	1
Hydroxyurea	increases expression	1
Manganese	increases abundance, increases 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_SP89	HAP1 GEN1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00092183	PHASE4	COMPLETED	An Investigational Drug for the Prevention of Chemotherapy-Induced Nausea and Vomiting (MK-0869-071)
NCT00128778	PHASE4	COMPLETED	Maintenance Treatment With Liposomal Doxorubicin (Caelyx) in Metastatic Breast Cancer Patients
NCT00302120	PHASE4	UNKNOWN	The MONET - Study: MR Mammography of Nonpalpable Breast Tumors
NCT00307606	PHASE4	UNKNOWN	Does a Single Steroid Injection Reduce the Formation of Postmastectomy Seroma
NCT00370240	PHASE4	COMPLETED	Chlorhydrate of Ropivacaine and Breast Cancer Surgery
NCT00375752	PHASE4	TERMINATED	Efficacy and Safety of Letrozole vs. Letrozole Plus Zoledronic Acid as Endocrine Therapy Before Surgery in Postmenopausal Patients With Breast Cancer
NCT00575354	PHASE4	COMPLETED	Comparison of Sevoflurane and Isoflurane Anesthesia for Benign Breast Tumor Excision
NCT00604968	PHASE4	TERMINATED	Pegylated Liposomal Doxorubicin (Caelyx(R)) as Monotherapy in Elderly Patients With Locally Advanced and/or Metastatic Breast Cancer (Study P05059)
NCT00616135	PHASE4	COMPLETED	Study of Autologous Fat Enhanced w/ Regenerative Cells Transplanted to Reconstruct Breast Deformities After Lumpectomy
NCT00649090	PHASE4	COMPLETED	A Study to Evaluate the Safety of Adjuvant Treatment With Exemestane Following Previous Treatment With Tamoxifen in Postmenopausal Women With Estrogen Sensitive Primary Breast Cancer
NCT00779285	PHASE4	TERMINATED	Safety Study of CAELYX in Patients With Metastatic Breast Cancer Previously Treated With Anthracyclines (Study P04057)(TERMINATED)
NCT01176916	PHASE4	COMPLETED	Aromasin® Interventional Study Of Early Invasive Breast Cancer Patients In China
NCT01427400	PHASE4	UNKNOWN	The Use of Botulinum Toxin A in Two-Stage Tissue Expander/ Implant Breast Reconstruction
NCT01849380	PHASE4	UNKNOWN	Neoadjuvant ECS Versus ECF in Local Advanced Breast Cancer
NCT01859936	PHASE4	COMPLETED	Will Preoperative MRI Breast in Women Under 56 Years With Breast Cancer Change Primary Treatment
NCT01948960	PHASE4	COMPLETED	Influence of Exceptional Patient Characteristics on Everolimus Exposure
NCT01961544	PHASE4	COMPLETED	Eribulin Mesylate Phase IV Clinical Trial in Korean Patients With Metastatic or Locally Advanced Breast Cancer
NCT01975064	PHASE4	COMPLETED	Cancer and Anesthesia: Survival After Radical Surgery - a Comparison Between Propofol or Sevoflurane Anesthesia
NCT02004834	PHASE4	ACTIVE_NOT_RECRUITING	Levobupivacaine and Lidocaine for Paravertebral Block Causes Greater Hemodynamic Oscillations Than Levobupivacaine
NCT02372305	PHASE4	WITHDRAWN	Comparison of FlexHD and Alloderm Outcomes in Breast Reconstructive Surgery
NCT02479347	PHASE4	COMPLETED	Wound Infections in Breast Cancer Surgery After Preoperative Skin Preparation With Chlorhexidine vs. Povidone-iodine
NCT02549677	PHASE4	COMPLETED	Epirubicin Versus Docetaxel Plus Cyclophosphamide in Lymph Node Negative, ER-positive, Her2-negative Breast Cancer
NCT02612870	PHASE4	UNKNOWN	Sienna+® Injection Time Study 4 Arms
NCT02627560	PHASE4	COMPLETED	The Effect of Topical Tranexamic Acid on Bleeding and Seroma Formation in After Undergoing Mastectomy
NCT02661932	PHASE4	COMPLETED	Fertility Preservation in Breast Cancer Patients
NCT02781259	PHASE4	UNKNOWN	Selective Lymph Node Dissection Using Fluorescent Dye in Node-positive Breast Cancer
NCT02819921	PHASE4	TERMINATED	Desvenlafaxine for Treatment of Hot Flashes in Women With Breast Cancer Taking Tamoxifen
NCT03220178	PHASE4	TERMINATED	Impact of eHealth-support on Quality of Life in Metastatic Breast Cancer Patients Treated With Palbociclib and Endocrine Therapy
NCT03583944	PHASE4	COMPLETED	A Study to Evaluate Safety, Tolerability and Efficacy of Eribulin Mesylate in Treating Adult Females With Locally Advanced or Metastatic Breast Cancer
NCT03586154	PHASE4	COMPLETED	Combined Intra-articular Shoulder Injection and Stellate Ganglion Block in Chronic Post-mastectomy Shoulder Pain
NCT04707196	PHASE4	COMPLETED	A Study of Abemaciclib in Indian Women With Advanced Breast Cancer
NCT04931615	PHASE4	COMPLETED	ARTISS a Single-centre Randomised Control Study
NCT05033769	PHASE4	UNKNOWN	Assessing ImmunoResponse Post Eribulin: Eribulin and Immunogenicity in Advanced Breast Cancer
NCT05036005	PHASE4	UNKNOWN	Neoadjuvant Ontruzant (SB3) in Patients With HER2-positive Early Breast Cancer: An Open-Label (NeoON)
NCT05452213	PHASE4	RECRUITING	Comprehensive Analysis of Spatial, Temporal and Molecular Patterns of Ribociclib Efficacy and Resistance in Advanced Breast Cancer Patients
NCT05465031	PHASE4	RECRUITING	Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)
NCT05949333	PHASE4	UNKNOWN	Reducing Neutropenia Incidence With Pegfilgrastim Administration on Day 3 After Chemotherapy
NCT07158164	PHASE4	RECRUITING	DPYD Pharmacogenomics and Fluoropyrimidine (FP) Dose-Adjustment
NCT07162259	PHASE4	NOT_YET_RECRUITING	Cohort Study on Sequential ADC Therapy in HR-positive/HER2-negative Advanced Breast Cancer
NCT00000611	PHASE3	COMPLETED	Women’s Health Initiative (WHI)