SMC5

Summary

SMC5 (structural maintenance of chromosomes 5, HGNC:20465) is a protein-coding gene on chromosome 9q21.12, encoding Structural maintenance of chromosomes protein 5 (Q8IY18). Core component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. It is a selective cancer dependency (DepMap: 73.8% of cell lines).

Enables DNA secondary structure binding activity. Involved in several processes, including DNA recombination; negative regulation by host of viral genome replication; and positive regulation of cell cycle process. Located in cell junction; chromosome; and nuclear body. Part of Smc5-Smc6 complex. Is active in nucleus. Implicated in mosaic variegated aneuploidy syndrome.

Source: NCBI Gene 23137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Atelis syndrome 2 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 149 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 43
• Cancer dependency (DepMap): dependent in 73.8% of screened cell lines
• MANE Select transcript: NM_015110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20465
Approved symbol	SMC5
Name	structural maintenance of chromosomes 5
Location	9q21.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0594
Ensembl gene	ENSG00000198887
Ensembl biotype	protein_coding
OMIM	609386
Entrez	23137

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000361138, ENST00000471372, ENST00000475540, ENST00000618375, ENST00000884400, ENST00000884401, ENST00000912972, ENST00000912973, ENST00000912974, ENST00000912975, ENST00000912976, ENST00000912977, ENST00000912978, ENST00000912979, ENST00000912980, ENST00000955050, ENST00000955051, ENST00000955052, ENST00000955053

RefSeq mRNA: 1 — MANE Select: NM_015110 NM_015110

CCDS: CCDS6632

Canonical transcript exons

ENST00000361138 — 25 exons

Exon	Start	End
ENSE00000637600	70344144	70344269
ENSE00000705822	70282422	70282583
ENSE00000705824	70286200	70286271
ENSE00000705826	70297966	70298221
ENSE00000705828	70300046	70300200
ENSE00000705835	70315446	70315578
ENSE00000705837	70318514	70318687
ENSE00000705839	70318794	70318963
ENSE00000705842	70323483	70323606
ENSE00000705852	70346605	70346649
ENSE00001021719	70278491	70278625
ENSE00001090034	70280759	70280899
ENSE00001128904	70264304	70264445
ENSE00001208218	70314742	70314836
ENSE00001208255	70277310	70277472
ENSE00001208257	70267923	70267975
ENSE00001386038	70305247	70305360
ENSE00001387981	70258978	70259263
ENSE00001404049	70352191	70354873
ENSE00003471096	70350376	70350471
ENSE00003485424	70347613	70347717
ENSE00003488425	70347066	70347161
ENSE00003538828	70347919	70348038
ENSE00003553322	70350114	70350293
ENSE00003598310	70324021	70324143

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.4740 / max 614.2295, expressed in 1801 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96871	19.2485	1776
96872	5.2254	1559

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.12	gold quality
calcaneal tendon	UBERON:0003701	96.50	gold quality
left ovary	UBERON:0002119	95.21	gold quality
ovary	UBERON:0000992	93.76	gold quality
right ovary	UBERON:0002118	93.59	gold quality
adrenal tissue	UBERON:0018303	93.24	gold quality
ventricular zone	UBERON:0003053	92.96	gold quality
body of pancreas	UBERON:0001150	92.25	gold quality
epithelium of nasopharynx	UBERON:0001951	92.08	gold quality
rectum	UBERON:0001052	92.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.63	gold quality
tendon	UBERON:0000043	91.16	gold quality
right lung	UBERON:0002167	91.04	gold quality
minor salivary gland	UBERON:0001830	90.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.64	gold quality
right uterine tube	UBERON:0001302	90.58	gold quality
tibial nerve	UBERON:0001323	90.56	gold quality
body of uterus	UBERON:0009853	90.26	gold quality
superior surface of tongue	UBERON:0007371	90.03	gold quality
colonic epithelium	UBERON:0000397	89.97	gold quality
ectocervix	UBERON:0012249	89.94	gold quality
vagina	UBERON:0000996	89.88	gold quality
monocyte	CL:0000576	89.87	gold quality
endocervix	UBERON:0000458	89.87	gold quality
tonsil	UBERON:0002372	89.83	gold quality
mononuclear cell	CL:0000842	89.76	gold quality
pylorus	UBERON:0001166	89.75	gold quality
cranial nerve II	UBERON:0000941	89.72	gold quality
mouth mucosa	UBERON:0003729	89.71	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6524	no	72.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

142 targeting SMC5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548N	99.98	71.94	4170
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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-141-3P	99.94	72.79	2421

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 73.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 27)

• 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)
• SMC5 is crucial for mitotic progression and maintenance of sister chromatid cohesion during mitosis. (PMID:19502785)
• 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 SMC5 protein is associated with hepatitis B. (PMID:28095508)
• 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 found that SMC5 protein interaction with papillomavirus E2 is mediated by SMC6. the SMC5/6 complex was found to be involved 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)
• The structural maintenance of chromosomes 5 is a possible biomarker for individualized treatment of colorectal cancer. (PMID:35894836)
• Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. (PMID:36333305)
• Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency. (PMID:36376394)
• In-frame deletion of SMC5 related with the phenotype of primordial dwarfism, chromosomal instability and insulin resistance. (PMID:36627765)
• 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

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pimr7	ENSDARG00000044282
mus_musculus	Smc5	ENSMUSG00000024943
drosophila_melanogaster	SMC5	FBGN0052438
caenorhabditis_elegans		WBGENE00016151

Paralogs (1): SMC6 (ENSG00000163029)

Protein

Protein identifiers

Structural maintenance of chromosomes protein 5 — Q8IY18 (reviewed: Q8IY18)

All UniProt accessions (1): Q8IY18

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the SMC5-SMC6 complex, a complex involved in repair of 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. Required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome.

Subunit / interactions. Forms a heterodimer with SMC6. Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. Interacts with NSMCE2. Interacts with SLF2; this interaction induces an association of the SLF1-SLF2 complex with the SMC5-SMC6 complex. Interacts with RAD18; this interaction is increased in a SLF1 or SLF2-dependent manner. (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.

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

Tissue specificity. Widely expressed. Strongly expressed in testis.

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

Disease relevance. Atelis syndrome 2 (ATELS2) [MIM:620185] A form of Atelis syndrome, an autosomal recessive neurodevelopmental disorder characterized by mild to severe developmental delay, learning difficulties, microcephaly, and growth restriction with short stature. Additional features include anemia, skin hyperpigmentation, ocular anomalies, congenital heart defects, and mild skeletal abnormalities. Death in childhood may occur. Patient cells show spontaneous chromosome breakage and chromosomal anomalies, hallmarked by segmented and dicentric chromosomes and mosaic variegated hyperploidy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC6, forming a V-shaped heterodimer.

Similarity. Belongs to the SMC family. SMC5 subfamily.

RefSeq proteins (1): NP_055925* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038729	Rad50/SbcC_AAA	Domain

Pfam: PF13476

UniProt features (16 total): sequence variant 6, coiled-coil region 3, region of interest 2, modified residue 2, chain 1, compositionally biased region 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-Q8IY18-F1	79.72	0.15

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): 80–87

Post-translational modifications (2): 25, 35

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: 397 (showing top): GOBP_CHROMOSOME_ORGANIZATION, MODULE_97, MORF_ATRX, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_TELOMERE_ORGANIZATION, MODULE_182, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELLULAR_SENESCENCE, GOBP_CHROMOSOME_CONDENSATION, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION

GO Biological Process (20): telomere maintenance via recombination (GO:0000722), double-strand break repair via homologous recombination (GO:0000724), DNA damage response (GO:0006974), chromosome segregation (GO:0007059), protein sumoylation (GO:0016925), stem cell population maintenance (GO:0019827), chromosome condensation (GO:0030261), regulation of telomere maintenance (GO:0032204), positive regulation of maintenance of mitotic sister chromatid cohesion (GO:0034184), mitotic cell cycle phase transition (GO:0044772), host-mediated suppression of viral genome replication (GO:0044828), cell division (GO:0051301), positive regulation of chromosome segregation (GO:0051984), protein localization to chromosome, centromeric region (GO:0071459), cellular senescence (GO:0090398), chromatin looping (GO:0140588), DNA repair (GO:0006281), double-strand break repair (GO:0006302), DNA recombination (GO:0006310), chromosome organization (GO:0051276)

GO Molecular Function (6): DNA secondary structure binding (GO:0000217), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), 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), cytoplasm (GO:0005737), PML body (GO:0016605), nuclear speck (GO:0016607), cell junction (GO:0030054), Smc5-Smc6 complex (GO:0030915), interchromatin granule (GO:0035061), site of double-strand break (GO:0035861), chromosome (GO:0005694)

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
cellular anatomical structure	3
telomere maintenance	2
cellular response to stress	2
cellular process	2
DNA metabolic process	2
DNA binding	2
chromosomal region	2
nuclear body	2
mitotic recombination	1
recombinational repair	1
double-strand break repair	1
cell cycle process	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
multicellular organismal process	1
maintenance of cell number	1
chromosome organization	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
maintenance of mitotic sister chromatid cohesion	1
positive regulation of maintenance of sister chromatid cohesion	1
regulation of maintenance of mitotic sister chromatid cohesion	1
mitotic cell cycle	1
cell cycle phase transition	1
mitotic cell cycle 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
protein localization to chromosome	1
chromatin organization	1
DNA damage response	1
DNA repair	1
organelle organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMC5	SMC6	Q96SB8	993
SMC5	NSMCE2	Q96MF7	988
SMC5	NSMCE3	Q96MG7	978
SMC5	NSMCE4A	Q9NXX6	956
SMC5	RAD18	Q9NS91	924
SMC5	EID3	Q8N140	910
SMC5	RAD17	O75943	858
SMC5	SMC3	Q9UQE7	846
SMC5	RAD21	O60216	838
SMC5	RAD9A	Q99638	815
SMC5	FANCM	Q8IYD8	777
SMC5	SLF1	Q9BQI6	772
SMC5	NFATC2IP	Q8NCF5	757
SMC5	SLF2	Q8IX21	756
SMC5	SMC4	Q9NTJ3	744
SMC5	RAD52	P43351	744

IntAct

60 interactions, top by confidence:

A	B	Type	Score
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
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
NSMCE1	SMC5	psi-mi:“MI:0914”(association)	0.760
NSMCE1	SMC5	psi-mi:“MI:0915”(physical association)	0.760
EID3	SMC5	psi-mi:“MI:0915”(physical association)	0.740
SLF2	SMC5	psi-mi:“MI:0915”(physical association)	0.710
SMC5	SLF2	psi-mi:“MI:0915”(physical association)	0.710
ZNF597	TASOR2	psi-mi:“MI:0914”(association)	0.640
SMC5	DISC1	psi-mi:“MI:0915”(physical association)	0.560
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
NSMCE1	PMF1	psi-mi:“MI:0914”(association)	0.530
PJA1	SMC5	psi-mi:“MI:0914”(association)	0.530
ZNF597	HCFC1	psi-mi:“MI:0914”(association)	0.530
SMC5	H1-1	psi-mi:“MI:0915”(physical association)	0.400
SMC5	H1-5	psi-mi:“MI:0915”(physical association)	0.400
Smc6	SMC5	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
NSMCE2	SMC5	psi-mi:“MI:0915”(physical association)	0.370
SMN1	SMC5	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1061): SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Co-fractionation), SMC5 (Co-fractionation), SMC5 (Co-fractionation), SMC5 (Co-fractionation), SMC5 (Co-fractionation), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), SMC5 (Affinity Capture-MS)

ESM2 similar proteins: E7F0W1, F1LVW7, J9VL63, O42649, O93308, O93309, O97593, O97594, P0C928, P24785, P42285, P50532, P50533, P97690, Q00737, Q0IIM3, Q14683, Q56YN8, Q5R4K5, Q5R606, Q5ZJY5, Q60446, Q61699, Q66HA8, Q7PKQ5, Q802R8, Q802R9, Q805A1, Q8CG46, Q8CG47, Q8IY18, Q8NDV3, Q8UUU2, Q90ZA1, Q920F6, Q924W5, Q92598, Q96MR6, Q96SB8, Q9CU62

Diamond homologs: E7F0W1, G5EG17, O58687, P53692, Q5ZJY5, Q802R9, Q805A1, Q8CG46, Q8IY18, Q97WH0, Q9HLR8, O93309, O97594, P97690, Q5R4K5, Q9CW03, Q9UQE7, A0AEJ1, A0L3I9, A1T0X6, A2RNA8, A3DHZ7, A3MY75, A4SC23, A4W4R3, A5F493, A6L3K9, A6VK88, A7N1F1, A8ACL2, A8YW44, A9MJU2, A9MX74, B0BRG1, B0TAL0, B0UUM0, B2VCE1, B3GZJ3, B4S937, B4SYA6

SIGNOR signaling

1 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 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	34.5×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
regulation of telomere maintenance	8	143.4×	3e-14
protein sumoylation	8	55.2×	9e-11
double-strand break repair via homologous recombination	10	33.2×	3e-11
DNA damage response	9	10.2×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	111
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2443706	NM_015110.4(SMC5):c.1110GAG[1] (p.Arg372del)	Pathogenic
2443707	NM_015110.4(SMC5):c.1273C>T (p.Arg425Ter)	Pathogenic
2443708	NM_015110.4(SMC5):c.2968C>G (p.His990Asp)	Pathogenic
4845894	NM_015110.4(SMC5):c.1694_1697del (p.Ser564_Tyr565insTer)	Likely pathogenic

SpliceAI

3627 predictions. Top by Δscore:

Variant	Effect	Δscore
9:70259261:CCTG:C	donor_loss	1.0000
9:70259262:CTG:C	donor_loss	1.0000
9:70259264:G:GG	donor_gain	1.0000
9:70264296:T:G	acceptor_gain	1.0000
9:70264297:A:AG	acceptor_gain	1.0000
9:70264298:A:G	acceptor_gain	1.0000
9:70264299:TTCA:T	acceptor_loss	1.0000
9:70264302:A:AG	acceptor_gain	1.0000
9:70264302:AG:A	acceptor_loss	1.0000
9:70264303:G:GA	acceptor_gain	1.0000
9:70264303:GA:G	acceptor_gain	1.0000
9:70264303:GAA:G	acceptor_gain	1.0000
9:70264303:GAAC:G	acceptor_gain	1.0000
9:70264303:GAACA:G	acceptor_gain	1.0000
9:70264441:A:G	donor_gain	1.0000
9:70264443:AAGGT:A	donor_loss	1.0000
9:70264444:AGGT:A	donor_loss	1.0000
9:70264446:G:GG	donor_gain	1.0000
9:70277469:TCAG:T	donor_loss	1.0000
9:70277470:CAGG:C	donor_loss	1.0000
9:70277471:AG:A	donor_loss	1.0000
9:70277472:GGT:G	donor_loss	1.0000
9:70277473:G:GA	donor_loss	1.0000
9:70277474:T:G	donor_loss	1.0000
9:70278485:CTCTA:C	acceptor_loss	1.0000
9:70278486:TCTA:T	acceptor_loss	1.0000
9:70278488:TAG:T	acceptor_loss	1.0000
9:70278489:A:AG	acceptor_gain	1.0000
9:70278489:AG:A	acceptor_gain	1.0000
9:70278490:G:A	acceptor_loss	1.0000

AlphaMissense

7317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:70264364:T:A	N82K	1.000
9:70264364:T:G	N82K	1.000
9:70264366:G:A	G83E	1.000
9:70264371:G:T	G85W	1.000
9:70264372:G:A	G85E	1.000
9:70264380:A:C	S88R	1.000
9:70264382:C:A	S88R	1.000
9:70264382:C:G	S88R	1.000
9:70277342:G:C	R138P	1.000
9:70278591:T:C	L215P	1.000
9:70347931:T:A	W928R	1.000
9:70347931:T:C	W928R	1.000
9:70348010:G:A	G954D	1.000
9:70350153:T:C	F977L	1.000
9:70350155:T:A	F977L	1.000
9:70350155:T:G	F977L	1.000
9:70350279:G:C	D1019H	1.000
9:70350280:A:C	D1019A	1.000
9:70350280:A:G	D1019G	1.000
9:70350280:A:T	D1019V	1.000
9:70350281:T:A	D1019E	1.000
9:70350281:T:G	D1019E	1.000
9:70350282:G:A	E1020K	1.000
9:70350283:A:G	E1020G	1.000
9:70350290:T:A	N1022K	1.000
9:70350290:T:G	N1022K	1.000
9:70350380:T:A	M1025K	1.000
9:70350380:T:G	M1025R	1.000
9:70350395:A:T	E1030V	1.000
9:70350398:G:C	R1031P	1.000

dbSNP variants (sampled 300 via entrez): RS1000020022 (9:70284705 A>G), RS1000032247 (9:70288119 G>A), RS1000098889 (9:70306562 G>A), RS1000112580 (9:70300210 T>G), RS1000151352 (9:70299686 A>G), RS1000158071 (9:70257148 G>T), RS1000170124 (9:70306261 T>C,G), RS1000178172 (9:70273832 A>C,G), RS1000183153 (9:70336115 C>T), RS1000187544 (9:70349784 A>C,G), RS1000218033 (9:70270395 A>G), RS1000254944 (9:70326277 G>A), RS1000290916 (9:70278652 ATTG>A), RS1000291618 (9:70270172 G>T), RS1000296667 (9:70332616 G>A)

Disease associations

OMIM: gene MIM:609386 | disease phenotypes: MIM:620185

GenCC curated gene-disease

Disease	Classification	Inheritance
Atelis syndrome 2	Strong	Autosomal recessive

Mondo (1): Atelis syndrome 2 (MONDO:0859576)

Orphanet (0):

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000448	Prominent nose
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia
HP:0000699	Diastema
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000842	Hyperinsulinemia
HP:0000954	Single transverse palmar crease
HP:0000960	Sacral dimple
HP:0001250	Seizure
HP:0001270	Motor delay
HP:0001298	Encephalopathy
HP:0001310	Dysmetria
HP:0001348	Brisk reflexes
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001763	Pes planus
HP:0001873	Thrombocytopenia
HP:0001903	Anemia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007335_19	Age at first sexual intercourse	7.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
pentanal	decreases expression	1
tamibarotene	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1
Coumestrol	decreases expression	1
Doxorubicin	increases expression	1

Clinical trials (associated diseases)

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