SPRTN

Summary

SPRTN (SprT-like N-terminal domain, HGNC:25356) is a protein-coding gene on chromosome 1q42.2, encoding DNA-dependent metalloprotease SPRTN (Q9H040). DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. It is a selective cancer dependency (DepMap: 82.4% of cell lines).

The protein encoded by this gene may play a role in DNA repair during replication of damaged DNA. This protein recruits valosin containing protein (p97) to stalled DNA replication forks where it may prevent excessive translesional DNA synthesis and limit the number of DNA-damage induced mutations. It may also be involved in replication-related G2/M-checkpoint regulation. Deficiency of a similar protein in mouse causes chromosomal instability and progeroid phenotypes. Mutations in this gene have been associated with Ruijs-Aalfs syndrome (RJALS). Alternatively spliced transcript variants have been identified.

Source: NCBI Gene 83932 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progeroid features-hepatocellular carcinoma predisposition syndrome (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 78 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 25
• Cancer dependency (DepMap): dependent in 82.4% of screened cell lines
• MANE Select transcript: NM_032018

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25356
Approved symbol	SPRTN
Name	SprT-like N-terminal domain
Location	1q42.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP547N043, Spartan, DVC1
Ensembl gene	ENSG00000010072
Ensembl biotype	protein_coding
OMIM	616086
Entrez	83932

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000008440, ENST00000295050, ENST00000366644, ENST00000391858, ENST00000469904, ENST00000492437, ENST00000885390

RefSeq mRNA: 3 — MANE Select: NM_032018 NM_001010984, NM_001261462, NM_032018

CCDS: CCDS1594, CCDS31054, CCDS58066

Canonical transcript exons

ENST00000295050 — 5 exons

Exon	Start	End
ENSE00000793174	231347797	231347925
ENSE00001409968	231338293	231338604
ENSE00001679056	231352610	231355023
ENSE00003462210	231351304	231351571
ENSE00003535165	231339769	231339868

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 86.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1509 / max 91.4816, expressed in 1787 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9050	7.4138	1769
9049	2.7371	1383

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	86.93	gold quality
secondary oocyte	CL:0000655	86.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.67	gold quality
calcaneal tendon	UBERON:0003701	84.70	gold quality
stromal cell of endometrium	CL:0002255	82.45	gold quality
gastrocnemius	UBERON:0001388	81.68	gold quality
muscle of leg	UBERON:0001383	81.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.37	gold quality
adrenal tissue	UBERON:0018303	78.93	gold quality
islet of Langerhans	UBERON:0000006	78.69	gold quality
ventricular zone	UBERON:0003053	78.54	gold quality
leukocyte	CL:0000738	77.97	gold quality
monocyte	CL:0000576	77.89	gold quality
smooth muscle tissue	UBERON:0001135	77.51	gold quality
bone marrow cell	CL:0002092	77.48	gold quality
right testis	UBERON:0004534	77.29	gold quality
testis	UBERON:0000473	77.23	gold quality
ganglionic eminence	UBERON:0004023	76.82	gold quality
left testis	UBERON:0004533	76.65	gold quality
vermiform appendix	UBERON:0001154	76.25	gold quality
lower esophagus mucosa	UBERON:0035834	75.88	gold quality
esophagus mucosa	UBERON:0002469	75.38	gold quality
cortical plate	UBERON:0005343	75.13	gold quality
granulocyte	CL:0000094	75.05	gold quality
epithelial cell of pancreas	CL:0000083	75.00	gold quality
gall bladder	UBERON:0002110	74.82	gold quality
left adrenal gland	UBERON:0001234	74.57	gold quality
esophagus	UBERON:0001043	74.33	gold quality
left adrenal gland cortex	UBERON:0035825	74.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting SPRTN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-5582-3P	99.86	72.48	4221

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 82.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 26)

• Spartan promotes an unexpected feed-forward loop to enhance PCNA ubiquitylation and translesion DNA synthesis. (PMID:22681887)
• Spartan is recruited to sites of stalled replication via ubiquitinated PCNA and plays an important role to prevent mutations associated with replication of damaged DNA. (PMID:22894931)
• C1orf124 acts at multiple steps in TLS, stabilizes RAD18 and ubiquitinated PCNA at damage sites, and facilitates the switch from replicative to TLS polymerase to bypass DNA lesion. (PMID:22902628)
• Authors propose that Spartan promotes genomic stability by regulating the choice of rescue of stalled replication fork, whose mechanism includes its interaction with ubiquitin-conjugated PCNA and protection against PCNA deubiquitylation. (PMID:22987070)
• DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. (PMID:23042605)
• DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. (PMID:23042607)
• The results suggest that Spartan negatively regulates POLD3 function in Rev1/Pol zeta-dependent translesion synthesis. (PMID:23254330)
• Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. (PMID:25261934)
• USP1, p21 and Spartan are translesion DNA synthesis regulators. (Review) (PMID:26002196)
• These findings offer new insights into the determinants of PIP box for PCNA binding. (PMID:27084448)
• DNA binding by SPARTAN regulates the targeting of Poleta to damage sites after UV exposure, and this function contributes highly to its DNA-damage tolerance function. (PMID:27838458)
• e show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)- a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs (PMID:27852435)
• Loss of SPRTN results in failure to repair DNA-protein crosslinks (DPCs) and hypersensitivity to DPC-inducing agents. (PMID:27871365)
• SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. (PMID:27871366)
• Spartan has a DNA-dependent protease activity degrading certain proteins bound to DNA. (PMID:28053116)
• the ZBD contributes to the ssDNA specificity of SPRTN, restricts the access of globular substrates, and positions DPCs, which may need to be partially unfolded, for optimal cleavage. (PMID:30893605)
• TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. (PMID:32152270)
• DNA Structure-Specific Cleavage of DNA-Protein Crosslinks by the SPRTN Protease. (PMID:32853547)
• A ubiquitin switch controls autocatalytic inactivation of the DNA-protein crosslink repair protease SPRTN. (PMID:33348378)
• SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells. (PMID:33558481)
• USP11 mediates repair of DNA-protein cross-links by deubiquitinating SPRTN metalloprotease. (PMID:33567341)
• Replication-dependent cytotoxicity and Spartan-mediated repair of trapped PARP1-DNA complexes. (PMID:34551432)
• The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability. (PMID:34879279)
• Ubiquitin-directed AAA+ ATPase p97/VCP unfolds stable proteins crosslinked to DNA for proteolysis by SPRTN. (PMID:35469923)
• SPRTN patient variants cause global-genome DNA-protein crosslink repair defects. (PMID:36681662)
• SPRTN is involved in hepatocellular carcinoma development through the ER stress response. (PMID:38086993)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sprtn	ENSDARG00000104709
mus_musculus	Sprtn	ENSMUSG00000031986
rattus_norvegicus	Sprtn	ENSRNOG00000021330
drosophila_melanogaster	mh	FBGN0267977
caenorhabditis_elegans		WBGENE00011834

Protein

Protein identifiers

DNA-dependent metalloprotease SPRTN — Q9H040 (reviewed: Q9H040)

Alternative names: DNA damage protein targeting VCP, Protein with SprT-like domain at the N terminus

All UniProt accessions (2): Q9H040, B1AKT1

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde. Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis. Catalyzes proteolytic cleavage of the HMCES DNA-protein cross-link following unfolding by the BRIP1/FANCJ helicase. Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4. Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs. SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs. Involved in recruitment of VCP/p97 to sites of DNA damage. Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation. Does not activate CHEK1 in response to DNA damage. May also act as a ‘reader’ of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis.

Subunit / interactions. Homodimer. Interacts (VIA PIP-box) with PCNA (when ubiquitinated). Interacts (via its SHP-box) with VCP/p97. Interacts with RAD18. Interacts with KCTD13 and POLD3.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Autocatalytically cleaved in response to double-stranded DNA-binding: autocatalytic cleavage takes place in trans and leads to inactivation. Monoubiquitinated; monoubiquitination promotes exclusion from chromatin. Deubiquitinated by VCPIP1: deubiquitination is required for subsequent acetylation and recruitment to chromatin and DNA damage sites. Acetylated following deubiquitination by VCPIP1, leading to recruitment to chromatin and DNA damage sites. Phosphorylation by CHEK1 promotes recruitment to chromatin.

Disease relevance. Ruijs-Aalfs syndrome (RJALS) [MIM:616200] A syndrome characterized by genomic instability, progeroid features, and susceptibility toward early onset hepatocellular carcinoma. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. DNA-binding activates the protease activity: single-stranded DNA-binding specifically activates ability to cleave covalent DNA-protein cross-links (DPCs). In contrast, double-stranded DNA-binding specifically activates autocatalytic cleavage, and subsequent inactivation.

Domain organisation. The PIP-box mediates the interaction with PCNA, while the UBZ4-type zinc finger mediates binding to ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin.

Similarity. Belongs to the Spartan family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H040-1	1	yes
Q9H040-2	2
Q9H040-3	3

RefSeq proteins (3): NP_001010984, NP_001248391, NP_114407* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006640	SprT-like_domain	Domain
IPR006642	Rad18_UBZ4	Domain
IPR044245	Spartan	Family
IPR055220	SPRTN_ZBD	Domain

Pfam: PF10263, PF22934

UniProt features (96 total): mutagenesis site 36, cross-link 11, helix 8, binding site 7, strand 7, modified residue 6, compositionally biased region 3, splice variant 3, short sequence motif 3, turn 3, region of interest 2, sequence variant 2, chain 1, domain 1, active site 1, site 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6MDW	X-RAY DIFFRACTION	1.5
6MDX	X-RAY DIFFRACTION	1.55
5IY4	X-RAY DIFFRACTION	2.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H040-F1	66.07	0.33

Functional residue map

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

Catalytic / active sites (2): 112; 227–228 (cleavage; by autolysis)

Ligand- & substrate-binding residues (7): 111; 115; 130; 456; 459; 471; 475

Post-translational modifications (17): 1, 230, 268, 373, 374, 383, 303, 341, 341, 361, 376, 376, 414, 423, 424, 435, 484

Mutagenesis-validated functional residues (36):

Position	Phenotype
71	abolished ability to mediate autocleavage. does not affect dna-binding.
91	abolished ability to mediate autocleavage. does not affect dna-binding.
112	abolished metalloprotease activity and ability to cleave covalent dna-protein cross-links (dpcs). abolished ability to c
149	abolished ability to mediate autocleavage in presence of ssdna.
153	abolished ability to mediate autocleavage in presence of ssdna.
155	abolished ability to mediate autocleavage in presence of ssdna.
156	abolished ability to mediate autocleavage in presence of ssdna.
157	increased ability to mediate autocleavage.
159	abolished ability to mediate autocleavage in presence of ssdna.
163	abolished ability to mediate autocleavage. strongly reduced dna-binding.
179	abolished metalloprotease activity and ability to mediate autocleavage. slightly impaired ability to cleave covalent dna
185	abolished metalloprotease activity and ability to cleave covalent dna-protein cross-links (dpcs).
189	abolished ability to mediate autocleavage. strongly reduced dna-binding.
194	strongly reduced ability to mediate autocleavage. strongly reduced dna-binding.
197	abolished metalloprotease activity, ability to cleave covalent dna-protein cross-links (dpcs) and to mediate autocleavag
211	strongly reduced ability to mediate autocleavage. strongly reduced dna-binding.
230	mimics acetylation, promoting cleavage of covalent dna-protein cross-links (dpcs).
230	abolished acetylation, leading to impaired localization to chromatin.
253	abolishes binding to vcp/p97; when associated with a-260.
260	abolishes binding to vcp/p97; when associated with a-253.
325–332	abolished interaction with pcna.
326	decreased interaction with pcna.
331–332	abolished interaction with pcna.
331	abolished interaction with pcna.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
R-HSA-73893	DNA Damage Bypass
R-HSA-73894	DNA Repair

MSigDB gene sets: 234 (showing top): GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_DNA_DAMAGE_TOLERANCE, GOBP_PROTEIN_MATURATION, GOBP_RESPONSE_TO_UV, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_DNA_BIOSYNTHETIC_PROCESS, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, DOUGLAS_BMI1_TARGETS_DN, REACTOME_DNA_REPAIR, MODULE_95, GOBP_DNA_REPLICATION, GOBP_RESPONSE_TO_LIGHT_STIMULUS

GO Biological Process (9): proteolysis (GO:0006508), DNA damage response (GO:0006974), response to UV (GO:0009411), protein autoprocessing (GO:0016540), translesion synthesis (GO:0019985), positive regulation of protein ubiquitination (GO:0031398), interstrand cross-link repair (GO:0036297), protein-DNA covalent cross-linking repair (GO:0106300), DNA repair (GO:0006281)

GO Molecular Function (13): double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin binding (GO:0043130), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), DNA binding (GO:0003677), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear speck (GO:0016607), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
DNA Damage Bypass	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA repair	2
DNA binding	2
cellular anatomical structure	2
protein metabolic process	1
cellular response to stress	1
response to light stimulus	1
protein processing	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
DNA metabolic process	1
DNA damage response	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
modification-dependent protein binding	1
ubiquitin-like protein binding	1
polyubiquitin modification-dependent protein binding	1
nucleic acid binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear ribonucleoprotein granule	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRTN	GCNA	Q96QF7	745
SPRTN	VCP	P55072	720
SPRTN	TDP1	Q9NUW8	715
SPRTN	TDP2	O95551	678
SPRTN	HMCES	Q96FZ2	672
SPRTN	TRAIP	Q9BWF2	662
SPRTN	RAD18	Q9NS91	606
SPRTN	FANCD2	Q9BXW9	555
SPRTN	USP1	O94782	555
SPRTN	TOP1	P11387	548
SPRTN	UBXN7	O94888	540
SPRTN	DDI1	Q8WTU0	536
SPRTN	REV3L	O60673	530
SPRTN	SDE2	Q6IQ49	508
SPRTN	RNF4	P78317	507

IntAct

15 interactions, top by confidence:

A	B	Type	Score
KPNA4	MYC	psi-mi:“MI:0915”(physical association)	0.780
XKRX	FAM234B	psi-mi:“MI:0914”(association)	0.530
GSTT1	MID1	psi-mi:“MI:0914”(association)	0.530
RANBP3L	SPRTN	psi-mi:“MI:0915”(physical association)	0.400
SPRTN	ENTREP1	psi-mi:“MI:0915”(physical association)	0.370
SPRTN	RALGAPA2	psi-mi:“MI:0914”(association)	0.350
EMC2	TBL2	psi-mi:“MI:0914”(association)	0.350
TMEM74	KLRG2	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	SDCBP	psi-mi:“MI:0914”(association)	0.350
GMCL2	APAF1	psi-mi:“MI:0914”(association)	0.350
SPRTN	SPOP	psi-mi:“MI:0914”(association)	0.350
SPRTN	ROCK2	psi-mi:“MI:0914”(association)	0.350
GMCL2	UBXN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (692): UBC (Reconstituted Complex), PCNA (Reconstituted Complex), UBC (Reconstituted Complex), BRAP (Affinity Capture-MS), BCL7C (Affinity Capture-MS), RALGAPA2 (Affinity Capture-MS), SPRTN (Affinity Capture-MS), SPRTN (Affinity Capture-MS), SPRTN (Affinity Capture-MS), SPRTN (Affinity Capture-MS), GTF2F1 (Affinity Capture-MS), SPRTN (Affinity Capture-MS), EIF4E2 (Affinity Capture-MS), NAPG (Affinity Capture-MS), PCNA (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2L7I0, A2VDP0, A2YX04, A5D979, B4FM28, B6SLJ0, D3ZVU1, F4I8S3, F4KFC7, F6UH96, G3X912, O01835, Q0J9J6, Q22557, Q24595, Q2HJG4, Q32LR5, Q38796, Q4KM91, Q53WJ1, Q5U3H2, Q65Z40, Q680Q4, Q6E3D5, Q6PI47, Q6Z8M8, Q700C2, Q7KW09, Q7XC57, Q7Y1C4, Q7Y1C5, Q7Z5K2, Q7ZXG4, Q801E2, Q8L840, Q8RY95, Q91W18, Q91ZX6, Q941B6, Q9BVC5

Diamond homologs: A0A0G2L7I0, A0A1L8G2K9, A5D979, D3ZVU1, F6UH96, G3X912, Q22557, Q9H040

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	49
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
143915	NM_032018.7(SPRTN):c.718_718+3del	Pathogenic
143916	NM_032018.7(SPRTN):c.350A>G (p.Tyr117Cys)	Pathogenic
162628	NM_032018.7(SPRTN):c.723del (p.Lys241fs)	Pathogenic
1809372	GRCh37/hg19 1q41-44(chr1:223972939-249224684)x3	Pathogenic
3239648	NM_032018.7(SPRTN):c.1246_1247del (p.Val416fs)	Likely pathogenic

SpliceAI

821 predictions. Top by Δscore:

Variant	Effect	Δscore
1:231338600:ACCCT:A	donor_gain	1.0000
1:231338605:G:GG	donor_gain	1.0000
1:231347795:A:AG	acceptor_gain	1.0000
1:231347796:G:GG	acceptor_gain	1.0000
1:231338601:CCCT:C	donor_gain	0.9900
1:231338602:CCT:C	donor_gain	0.9900
1:231338603:CT:C	donor_gain	0.9900
1:231338605:G:GC	donor_loss	0.9900
1:231338606:TGA:T	donor_loss	0.9900
1:231338607:GAGT:G	donor_loss	0.9900
1:231338608:AGTTC:A	donor_loss	0.9900
1:231339864:TAGAG:T	donor_loss	0.9900
1:231339865:AGAG:A	donor_loss	0.9900
1:231339867:AGGTA:A	donor_loss	0.9900
1:231339868:GG:G	donor_loss	0.9900
1:231339869:GT:G	donor_loss	0.9900
1:231339870:T:G	donor_loss	0.9900
1:231347791:TTCCA:T	acceptor_loss	0.9900
1:231347792:TCCAG:T	acceptor_loss	0.9900
1:231347793:CCAG:C	acceptor_loss	0.9900
1:231347794:CAGAC:C	acceptor_loss	0.9900
1:231347795:AG:A	acceptor_loss	0.9900
1:231347796:GAC:G	acceptor_gain	0.9900
1:231347796:GACC:G	acceptor_gain	0.9900
1:231347921:TAACG:T	donor_loss	0.9900
1:231347922:AACGG:A	donor_loss	0.9900
1:231347923:ACGG:A	donor_loss	0.9900
1:231347924:CGGTA:C	donor_loss	0.9900
1:231347925:GGTAT:G	donor_loss	0.9900
1:231347926:G:A	donor_loss	0.9900

AlphaMissense

3249 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:231347875:T:C	F134L	1.000
1:231347877:T:A	F134L	1.000
1:231347877:T:G	F134L	1.000
1:231347876:T:C	F134S	0.999
1:231347876:T:G	F134C	0.999
1:231347894:G:C	R140P	0.999
1:231351356:G:C	R168P	0.998
1:231351358:T:A	C169S	0.998
1:231351358:T:C	C169R	0.998
1:231351359:G:C	C169S	0.998
1:231339824:A:C	S93R	0.997
1:231339826:C:A	S93R	0.997
1:231339826:C:G	S93R	0.997
1:231347830:T:C	F119L	0.997
1:231347832:T:A	F119L	0.997
1:231347832:T:G	F119L	0.997
1:231347921:T:A	I149K	0.997
1:231351352:T:A	W167R	0.997
1:231351352:T:C	W167R	0.997
1:231338585:T:A	W68R	0.996
1:231338585:T:C	W68R	0.996
1:231339837:T:C	L97S	0.996
1:231339846:G:C	R100T	0.996
1:231347801:T:C	L109P	0.996
1:231347806:C:G	H111D	0.996
1:231347816:T:A	I114K	0.996
1:231347818:C:G	H115D	0.996
1:231347897:T:G	I141S	0.996
1:231347921:T:G	I149R	0.996
1:231351354:G:C	W167C	0.996

dbSNP variants (sampled 300 via entrez): RS1000012705 (1:231338047 T>A,G), RS1000067196 (1:231350913 G>A), RS1000353208 (1:231350488 T>C), RS1000404617 (1:231347735 A>C), RS1000496272 (1:231346056 C>G,T), RS1000706610 (1:231354261 TA>T,TAA), RS1000769043 (1:231346434 T>C,G), RS1001046222 (1:231339640 G>A,T), RS1001131927 (1:231345814 G>T), RS1001235256 (1:231348086 A>G), RS1001476276 (1:231352448 C>T), RS1001512647 (1:231346714 G>A), RS1001847931 (1:231345202 A>C,G), RS1002293668 (1:231346467 A>C,G), RS1002384584 (1:231346354 A>C)

Disease associations

OMIM: gene MIM:616086 | disease phenotypes: MIM:616200

GenCC curated gene-disease

Disease	Classification	Inheritance
progeroid features-hepatocellular carcinoma predisposition syndrome	Strong	Autosomal recessive

Mondo (2): progeroid features-hepatocellular carcinoma predisposition syndrome (MONDO:0014527), oligospermia (MONDO:0001913)

Orphanet (1): Progeroid features-hepatocellular carcinoma predisposition syndrome (Orphanet:435953)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000518	Cataract
HP:0000767	Pectus excavatum
HP:0000939	Osteoporosis
HP:0000954	Single transverse palmar crease
HP:0001402	Hepatocellular carcinoma
HP:0001763	Pes planus
HP:0002007	Frontal bossing
HP:0002216	Premature graying of hair
HP:0002750	Delayed skeletal maturation
HP:0002987	Elbow flexion contracture
HP:0003202	Skeletal muscle atrophy
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0005659	Thoracic kyphoscoliosis
HP:0007787	Posterior subcapsular cataract
HP:0008070	Sparse hair
HP:0009125	Lipodystrophy
HP:0030084	Clinodactyly
HP:0200021	Down-sloping shoulders
HP:0000798	Oligozoospermia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002383_153	Hematocrit	3.000000e-31
GCST90002384_32	Hemoglobin	2.000000e-25

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
methylparaben	decreases expression	1
butyraldehyde	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CPG-oligonucleotide	increases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nitrogen Mustard Compounds	affects reaction, increases expression	1
Quercetin	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Cyclosporine	increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT05158114	PHASE1	WITHDRAWN	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Testicular Injury and Oligospermia
NCT02063256	PHASE2/PHASE3	UNKNOWN	7 NUTS Study. Diet Modification and Male Fertility.
NCT06869863	PHASE1/PHASE2	RECRUITING	Study of Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of the Medicinal Product MediReg®
NCT00479960	EARLY_PHASE1	UNKNOWN	A Preliminary Study on Effect of Omega-3 on Human Sperm
NCT06342856	EARLY_PHASE1	UNKNOWN	Evaluation of Treatment With Coenzyme Q10 and L-Carnitine on Semen Parameters in Infertile Men With Idiopathic Oligoasthenoteratospermia
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01239186	Not specified	COMPLETED	Identification and Characterization of the Methylation Abnormalities on Whole Genome Among Infertile Men
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT01520584	Not specified	UNKNOWN	Supplement Intake in Infertile Men;the Effect on Sperm Parameters,Fertilization Rate and Embryo Quality
NCT01828710	Not specified	COMPLETED	Myo-inositol on Human Semen Parameters
NCT01856361	Not specified	TERMINATED	Ramipril for the Treatment of Oligospermia
NCT02155179	Not specified	COMPLETED	Sperm Pathology Samples and Morphokinetics
NCT03898752	Not specified	COMPLETED	Is Oxidative Stress in Semen Reduced by Lifestyle Intervention
NCT04349345	Not specified	COMPLETED	Seminal Fluid’s Changes Over 20 Years
NCT04795440	Not specified	COMPLETED	Comparison of ICSI Outcomes in Cycles Using Testicular and Ejaculate Sperm From Couples With High SDF
NCT05506722	Not specified	UNKNOWN	Using of Testes Shocker in Improving the Spermatogenesis and Sperms Activity
NCT05842239	Not specified	RECRUITING	Hyperbaric Oxygen Therapy for Men Suffering From Infertility Due to Oligospermia.
NCT06202469	Not specified	COMPLETED	Creatine and Ubiquinol for Sperm Quality
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)