SMC6

Summary

SMC6 (structural maintenance of chromosomes 6, HGNC:20466) is a protein-coding gene on chromosome 2p24.2, encoding Structural maintenance of chromosomes protein 6 (Q96SB8). Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. It is a selective cancer dependency (DepMap: 54.1% of cell lines).

Enables DNA secondary structure binding activity and ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; negative regulation by host of viral genome replication; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. Is active in nucleus.

Source: NCBI Gene 79677 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 114 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 54.1% of screened cell lines
• MANE Select transcript: NM_001142286

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20466
Approved symbol	SMC6
Name	structural maintenance of chromosomes 6
Location	2p24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22116
Ensembl gene	ENSG00000163029
Ensembl biotype	protein_coding
OMIM	609387
Entrez	79677

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 17 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000351948, ENST00000381272, ENST00000402989, ENST00000428868, ENST00000430591, ENST00000446852, ENST00000448223, ENST00000481708, ENST00000489535, ENST00000621152, ENST00000861876, ENST00000861877, ENST00000922960, ENST00000922961, ENST00000922962, ENST00000922963, ENST00000960848, ENST00000960849, ENST00000960850, ENST00000960851

RefSeq mRNA: 2 — MANE Select: NM_001142286 NM_001142286, NM_024624

CCDS: CCDS1690

Canonical transcript exons

ENST00000448223 — 28 exons

Exon	Start	End
ENSE00001070784	17721142	17721261
ENSE00001070787	17720940	17721038
ENSE00001070789	17716086	17716264
ENSE00001070790	17714861	17715065
ENSE00001070791	17717088	17717176
ENSE00001070793	17738221	17738326
ENSE00001070794	17731078	17731139
ENSE00001070795	17700208	17700378
ENSE00001070796	17701829	17701909
ENSE00001070798	17718077	17718223
ENSE00001070799	17707219	17707379
ENSE00001070800	17741612	17741729
ENSE00001070803	17725257	17725358
ENSE00001070804	17716741	17716905
ENSE00001070805	17726389	17726469
ENSE00001070807	17731741	17731877
ENSE00001070808	17696289	17696426
ENSE00001070828	17678859	17678964
ENSE00001162677	17683638	17683763
ENSE00001162683	17695152	17695297
ENSE00001226642	17663812	17665613
ENSE00001391541	17745827	17745951
ENSE00001488025	17752978	17753064
ENSE00001855732	17753626	17753810
ENSE00003470935	17708639	17708753
ENSE00003553823	17670423	17670575
ENSE00003585691	17666420	17666517
ENSE00003784907	17703157	17703292

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0915 / max 161.6393, expressed in 1792 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27040	9.7108	1751
27039	4.2596	1461
27038	0.1144	35
27041	0.0066	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.57	gold quality
male germ cell	CL:0000015	96.62	gold quality
secondary oocyte	CL:0000655	95.60	gold quality
calcaneal tendon	UBERON:0003701	93.30	gold quality
pigmented layer of retina	UBERON:0001782	93.19	gold quality
left testis	UBERON:0004533	91.98	gold quality
right testis	UBERON:0004534	91.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.53	gold quality
testis	UBERON:0000473	91.43	gold quality
oocyte	CL:0000023	89.89	gold quality
corpus epididymis	UBERON:0004359	87.86	gold quality
tendon	UBERON:0000043	87.50	gold quality
choroid plexus epithelium	UBERON:0003911	87.47	gold quality
ventricular zone	UBERON:0003053	86.43	gold quality
rectum	UBERON:0001052	86.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.75	gold quality
right lobe of liver	UBERON:0001114	85.67	gold quality
colonic epithelium	UBERON:0000397	85.55	gold quality
minor salivary gland	UBERON:0001830	85.44	gold quality
esophagus mucosa	UBERON:0002469	85.27	gold quality
stromal cell of endometrium	CL:0002255	85.22	gold quality
skin of hip	UBERON:0001554	84.30	gold quality
vagina	UBERON:0000996	84.28	gold quality
tonsil	UBERON:0002372	84.21	gold quality
adenohypophysis	UBERON:0002196	84.13	gold quality
vermiform appendix	UBERON:0001154	84.05	gold quality
ganglionic eminence	UBERON:0004023	84.03	gold quality
right uterine tube	UBERON:0001302	83.96	gold quality
mouth mucosa	UBERON:0003729	83.72	gold quality
caput epididymis	UBERON:0004358	83.45	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting SMC6, 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-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 54.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells (PMID:16055714)
• SMC5/6 complex is recruited to nuclease-induced double-strand breaks (DSBs) and is required for the recruitment of cohesin to DSBs. (PMID:16810316)
• SMC5/6 complex facilitates telomere homologous recombination and elongation in alternative lengthening of telomeres cells through SUMOylation of telomere-binding proteins. (PMID:17589526)
• The four non-SMC components of the human complex were identified and characterized and it was demonstrated that the MAGEG1 protein is part of this complex. (PMID:18086888)
• Nse1 RING-like motif is a protein-protein interaction domain required for Smc5-Smc6 holocomplex integrity and recruitment to, or retention at, DNA lesions (PMID:18667531)
• Studies indicate that Nse1 may function as a ubiquitin ligase, and is targeted to chromatin through its interaction with the Smc5/6 complex. (PMID:21550342)
• Depletion of Smc5 and Smc6 resulted in aberrant mitotic chromosome phenotypes that were accompanied by the abnormal distribution of topoisomerase IIalpha (topo IIalpha) and condensins and by chromosome segregation errors (PMID:24258023)
• Structural maintenance of chromosomes (SMC) complexes, which in eukaryotic cells include cohesin, condensin and the Smc5/6 complex, are central regulators of chromosome dynamics (PMID:25145851)
• results uncover a novel role for the Smc5/6 complex as a restriction factor selectively blocking extrachromosomal DNA transcription; by destroying this complex, HBx relieves the inhibition to allow productive hepatitis B virus gene expression (PMID:26983541)
• SMC5/6 knockdown rescued HBx-deficient hepatitis b virus replication in human hepatocytes. (PMID:27626656)
• The SMC5/6 complex physically interacts with the DNA topoisomerase II alpha (TOP2A). (PMID:27792189)
• High SMC6 protein is associated with hepatitis B. (PMID:28095508)
• Brazilian Amerindian ancestry compared to Asian, European, and African Genomes.SNPs within or proximal to CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch. SNPs in ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) in the Asian comparison. (PMID:28100790)
• Study shows that the SMC5/6-hinge complex binds preferentially to ssDNA and that this interaction is affected by both ’latch’ and ‘hub’ mutations, suggesting a key role for these unique features in controlling DNA association by the SMC5/6 complex. (PMID:28134253)
• Data suggest that SMC6 is not required for papillomavirus E2-mediated transcriptional activation, E1/E2-mediated transient replication, or differentiation-dependent amplification of viral DNA. However, a role for SMC5/6 complex was found in the papillomavirus genome maintenance. (PMID:29848583)
• SMC5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability. (PMID:31867888)
• Inducible Degradation of the Human SMC5/6 Complex Reveals an Essential Role Only during Interphase. (PMID:32320646)
• Molecular Insights into the Architecture of the Human SMC5/6 Complex. (PMID:32389690)
• The Smc5/6 Core Complex Is a Structure-Specific DNA Binding and Compacting Machine. (PMID:33301731)
• The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr. (PMID:33811831)
• Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency. (PMID:36376394)
• The SMC5/6 complex: folding chromosomes back into shape when genomes take a break. (PMID:38375830)
• The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress. (PMID:38886582)
• Human Smc5/6 recognises transcription-generated positive DNA supercoils. (PMID:39242537)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-119f1.1	ENSDARG00000058719
mus_musculus	Smc6	ENSMUSG00000020608
rattus_norvegicus	Smc6	ENSRNOG00000004908
drosophila_melanogaster	SMC6	FBGN0266282
caenorhabditis_elegans		WBGENE00007694
caenorhabditis_elegans		WBGENE00010056

Paralogs (1): SMC5 (ENSG00000198887)

Protein

Protein identifiers

Structural maintenance of chromosomes protein 6 — Q96SB8 (reviewed: Q96SB8)

All UniProt accessions (7): A0A087WWI9, A0A0A0MRY1, A0A2S1ZR87, C9JEF0, C9JMN1, Q96SB8, H7C3J8

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome.

Subunit / interactions. Forms a heterodimer with SMC5. Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. Interacts with NSMCE1. Interacts with NSMCE2. Interacts with SLF1. Interacts with SLF2. Interacts with RAD18. Interacts with SIMC1. (Microbial infection) SMC5-SMC6 complex interacts with Hepatitis B X protein. (Microbial infection) Interacts with human herpesvirus 8 (KSHV) protein RTA/ORF50; this interaction targets the SMC5-SMC6 complex for proteasomal degradation. (Microbial infection) Interacts with Epstein-Barr virus BNRF1; this interaction targets SMC5-SMC6 complex for proteasomal degradation.

Subcellular location. Nucleus. Nucleus speckle. Chromosome. PML body. Telomere.

Tissue specificity. Widely expressed. Strongly expressed in testis.

Post-translational modifications. Phosphorylated. Sumoylated by NSMCE2/MMS21. Ubiquitinated. (Microbial infection) SMC5-SMC6 complex is degraded by the activity of Hepatitis B X protein.

Domain organisation. The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC5, forming a V-shaped heterodimer.

Similarity. Belongs to the SMC family. SMC6 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96SB8-1	1	yes
Q96SB8-2	2

RefSeq proteins (2): NP_001135758, NP_078900 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003395	RecF/RecN/SMC_N	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF02463

UniProt features (22 total): sequence variant 5, region of interest 4, sequence conflict 3, cross-link 2, coiled-coil region 2, compositionally biased region 2, chain 1, modified residue 1, splice variant 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9LWI	ELECTRON MICROSCOPY	3.12
9LWJ	ELECTRON MICROSCOPY	7.19
9LWL	ELECTRON MICROSCOPY	7.25
9LWK	ELECTRON MICROSCOPY	7.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96SB8-F1	80.20	0.25

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 (1): 76–83

Post-translational modifications (3): 669, 268, 773

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 272 (showing top): E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_TELOMERE_ORGANIZATION, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_CELLULAR_SENESCENCE, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, CEBPB_01, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_PEPTIDYL_LYSINE_MODIFICATION

GO Biological Process (12): telomere maintenance via recombination (GO:0000722), double-strand break repair via homologous recombination (GO:0000724), DNA damage response (GO:0006974), protein sumoylation (GO:0016925), regulation of telomere maintenance (GO:0032204), host-mediated suppression of viral genome replication (GO:0044828), positive regulation of chromosome segregation (GO:0051984), cellular senescence (GO:0090398), chromatin looping (GO:0140588), DNA repair (GO:0006281), double-strand break repair (GO:0006302), DNA recombination (GO:0006310)

GO Molecular Function (8): DNA secondary structure binding (GO:0000217), damaged DNA binding (GO:0003684), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ubiquitin protein ligase binding (GO:0031625), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (13): chromosome, centromeric region (GO:0000775), chromosome, telomeric region (GO:0000781), sex chromosome (GO:0000803), nucleus (GO:0005634), nucleoplasm (GO:0005654), PML body (GO:0016605), nuclear speck (GO:0016607), Smc5-Smc6 complex (GO:0030915), interchromatin granule (GO:0035061), site of double-strand break (GO:0035861), mitotic spindle pole (GO:0097431), chromosome (GO:0005694), chromosomal region (GO:0098687)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA binding	3
telomere maintenance	2
cellular response to stress	2
DNA metabolic process	2
chromosomal region	2
chromosome	2
cellular anatomical structure	2
nuclear body	2
mitotic recombination	1
recombinational repair	1
double-strand break repair	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
viral genome replication	1
host-mediated perturbation of viral process	1
chromosome segregation	1
regulation of chromosome segregation	1
positive regulation of cell cycle process	1
cellular process	1
chromatin organization	1
DNA damage response	1
DNA repair	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
ubiquitin-like protein ligase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear ribonucleoprotein granule	1
condensed chromosome	1
SUMO ligase complex	1
site of DNA damage	1
spindle pole	1
mitotic spindle	1

Protein interactions and networks

STRING

2718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMC6	NSMCE3	Q96MG7	994
SMC6	SMC5	Q8IY18	993
SMC6	NSMCE2	Q96MF7	983
SMC6	NSMCE4A	Q9NXX6	972
SMC6	RAD9A	Q99638	821
SMC6	RAD21	O60216	800
SMC6	EID3	Q8N140	798
SMC6	NSMCE1	Q8WV22	788
SMC6	RAD18	Q9NS91	777
SMC6	SMC4	Q9NTJ3	758
SMC6	RAD17	O75943	754
SMC6	SMC3	Q9UQE7	734
SMC6	CHEK2	O96017	726
SMC6	RAD52	P43351	688
SMC6	MUS81	Q96NY9	681

IntAct

71 interactions, top by confidence:

A	B	Type	Score
NSMCE3	NSMCE1	psi-mi:“MI:0914”(association)	0.970
SMC5	SMC6	psi-mi:“MI:0407”(direct interaction)	0.860
SMC6	SMC5	psi-mi:“MI:0914”(association)	0.860
SMC5	SMC6	psi-mi:“MI:0915”(physical association)	0.860
EID3	NSMCE1	psi-mi:“MI:0914”(association)	0.830
SMC6	NSMCE1	psi-mi:“MI:0915”(physical association)	0.810
NSMCE1	SMC6	psi-mi:“MI:0915”(physical association)	0.810
SMC6	NSMCE3	psi-mi:“MI:0915”(physical association)	0.770
NSMCE1	SMC5	psi-mi:“MI:0914”(association)	0.760
NSMCE1	SMC5	psi-mi:“MI:0915”(physical association)	0.760
SLF2	SMC6	psi-mi:“MI:0915”(physical association)	0.750
SMC6	SLF2	psi-mi:“MI:0915”(physical association)	0.750
SIMC1	SLF2	psi-mi:“MI:0914”(association)	0.750
EID3	SMC5	psi-mi:“MI:0915”(physical association)	0.740
NSMCE4A	NSMCE1	psi-mi:“MI:0914”(association)	0.740
NSMCE2	SMC6	psi-mi:“MI:0915”(physical association)	0.710
NSMCE1	NSMCE2	psi-mi:“MI:0914”(association)	0.710
IFT25	IFT56	psi-mi:“MI:0914”(association)	0.690
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
HSF1	KPNA3	psi-mi:“MI:0914”(association)	0.640
ZNF597	HCFC1	psi-mi:“MI:0914”(association)	0.530
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
NSMCE1	PMF1	psi-mi:“MI:0914”(association)	0.530

BioGRID (167): SMC6 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), SMC5 (Co-fractionation), SMC6 (Co-fractionation), SMC6 (Co-fractionation), SMC6 (Co-fractionation), SMC6 (Affinity Capture-MS), SMC6 (Proximity Label-MS), ZFP36L2 (Affinity Capture-MS), BTF3 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GVF0, A0A1L8GXM0, A0A8M9PQ61, A2ZAC2, G0SHW7, G5EG17, O14777, O44199, O94383, O95347, P12753, P38989, P41003, P48996, P53692, P70388, Q09591, Q10173, Q12267, Q12749, Q196W6, Q336R3, Q4R630, Q503N2, Q54PK4, Q5U4X5, Q6DRJ7, Q6GQ71, Q6P9I7, Q6Q1P4, Q76I89, Q76I90, Q7ZW63, Q802R8, Q8AWF4, Q8AWF5, Q8CG48, Q90988, Q924W5, Q92878

Diamond homologs: A0Q5W0, A2RNA8, A3DHZ7, A4IJ87, A4IXB4, A4SC23, A5D6E6, A7GJS2, A7ND52, B0S909, B0SK33, B0U178, B2A2Y9, B2SG84, B4S937, B8FXW8, B8I3R5, C5BKM1, C5D330, D4GUK1, O29230, O33600, O58687, P58301, P58302, P62134, Q02WH8, Q03I57, Q03UE1, Q040E6, Q0BL82, Q14I72, Q18C86, Q252K0, Q254F3, Q2A2N7, Q2S6G1, Q3A8P5, Q58718, Q5JHN1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SMC6	“form complex”	SMC5/6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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
SUMOylation of DNA damage response and repair proteins	8	27.2×	1e-07
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	17.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of telomere maintenance	8	120.4×	5e-13
protein sumoylation	7	40.5×	4e-08
double-strand break repair via homologous recombination	9	25.1×	1e-08
protein import into nucleus	5	12.9×	2e-03
DNA repair	9	10.3×	2e-05
DNA damage response	10	9.6×	7e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	85
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1180531	GRCh37/hg19 2p24.3-24.1(chr2:15640273-19609496)x1	Pathogenic

SpliceAI

7408 predictions. Top by Δscore:

Variant	Effect	Δscore
2:17665609:GTGAA:G	acceptor_gain	1.0000
2:17665610:TGAA:T	acceptor_gain	1.0000
2:17665611:GAA:G	acceptor_gain	1.0000
2:17665614:C:CC	acceptor_gain	1.0000
2:17666415:GTTAC:G	donor_loss	1.0000
2:17666416:TTACC:T	donor_loss	1.0000
2:17666417:TACC:T	donor_loss	1.0000
2:17666419:C:CA	donor_loss	1.0000
2:17666514:TATC:T	acceptor_gain	1.0000
2:17666516:TC:T	acceptor_gain	1.0000
2:17666517:CC:C	acceptor_gain	1.0000
2:17666517:CCTGA:C	acceptor_loss	1.0000
2:17666518:C:CA	acceptor_loss	1.0000
2:17666518:C:CC	acceptor_gain	1.0000
2:17683636:A:AC	donor_gain	1.0000
2:17683636:AC:A	donor_gain	1.0000
2:17683637:C:CA	donor_gain	1.0000
2:17683637:CC:C	donor_gain	1.0000
2:17683637:CCTT:C	donor_gain	1.0000
2:17683760:CTGC:C	acceptor_gain	1.0000
2:17695147:CTTA:C	donor_loss	1.0000
2:17695148:TTA:T	donor_loss	1.0000
2:17695149:TA:T	donor_loss	1.0000
2:17695150:A:AC	donor_gain	1.0000
2:17695150:AC:A	donor_gain	1.0000
2:17695151:C:CT	donor_gain	1.0000
2:17695151:CC:C	donor_gain	1.0000
2:17695151:CCT:C	donor_gain	1.0000
2:17695295:CTC:C	acceptor_gain	1.0000
2:17695297:CCT:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003830 (2:17670021 G>A), RS1000079880 (2:17694073 T>C), RS1000167916 (2:17733154 A>G), RS1000181608 (2:17690208 T>C), RS1000274877 (2:17734251 C>G,T), RS1000347098 (2:17676629 C>A), RS1000411617 (2:17720293 C>T), RS1000447321 (2:17683153 T>A,G), RS1000546799 (2:17710174 G>A), RS1000563116 (2:17752859 T>C), RS1000569303 (2:17691112 T>C), RS1000575932 (2:17734120 G>T), RS1000701412 (2:17689941 T>C), RS1000710730 (2:17696788 G>A,C), RS1000840204 (2:17722532 G>A)

Disease associations

OMIM: gene MIM:609387 | disease phenotypes: MIM:601086

GenCC curated gene-disease

Mondo (1): laterality defects, autosomal dominant (MONDO:0010991)

Orphanet (1): Visceral heterotaxy (Orphanet:450)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006614_11	Total cholesterol levels	1.000000e-08
GCST008078_125	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-08
GCST008079_126	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-09
GCST008086_74	LDL cholesterol levels in current drinkers	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563391	Laterality Defects, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation	1
kojic acid	decreases expression	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1
tianma gouteng yin	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Ascorbic Acid	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Copper	affects binding, decreases expression	1

Clinical trials (associated diseases)

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