SYCP3

Summary

SYCP3 (synaptonemal complex protein 3, HGNC:18130) is a protein-coding gene on chromosome 12q23.2, encoding Synaptonemal complex protein 3 (Q8IZU3). Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase.

This gene encodes an essential structural component of the synaptonemal complex. This complex is involved in synapsis, recombination and segregation of meiotic chromosomes. Mutations in this gene are associated with azoospermia in males and susceptibility to pregnancy loss in females. Alternate splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 50511 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infertility disorder (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 64 total — 3 pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_001177949

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18130
Approved symbol	SYCP3
Name	synaptonemal complex protein 3
Location	12q23.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139351
Ensembl biotype	protein_coding
OMIM	604759
Entrez	50511

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000266743, ENST00000392924, ENST00000392927, ENST00000478139, ENST00000478238

RefSeq mRNA: 3 — MANE Select: NM_001177949 NM_001177948, NM_001177949, NM_153694

CCDS: CCDS9087

Canonical transcript exons

ENST00000392924 — 9 exons

Exon	Start	End
ENSE00000937683	101733575	101733674
ENSE00001267500	101737037	101737071
ENSE00001267508	101737232	101737298
ENSE00001513624	101737803	101737952
ENSE00001513625	101739351	101739462
ENSE00003461795	101728648	101728980
ENSE00003481038	101729109	101729213
ENSE00003501986	101731568	101731666
ENSE00003502132	101734927	101735044

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 97.43.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2055 / max 134.5153, expressed in 8 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132903	0.2055	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	97.43	gold quality
left testis	UBERON:0004533	96.80	gold quality
secondary oocyte	CL:0000655	95.88	gold quality
testis	UBERON:0000473	95.21	gold quality
oocyte	CL:0000023	94.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.71	gold quality
sperm	CL:0000019	91.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.28	gold quality
adult organism	UBERON:0007023	84.89	gold quality
lower esophagus mucosa	UBERON:0035834	79.07	gold quality
oviduct epithelium	UBERON:0004804	75.35	gold quality
buccal mucosa cell	CL:0002336	73.00	silver quality
stromal cell of endometrium	CL:0002255	70.58	gold quality
mucosa of transverse colon	UBERON:0004991	68.86	gold quality
adrenal tissue	UBERON:0018303	67.58	gold quality
calcaneal tendon	UBERON:0003701	67.29	gold quality
cerebellar hemisphere	UBERON:0002245	66.77	gold quality
cerebellar cortex	UBERON:0002129	66.60	gold quality
cortical plate	UBERON:0005343	66.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.80	gold quality
ventricular zone	UBERON:0003053	65.73	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.50	gold quality
minor salivary gland	UBERON:0001830	65.34	gold quality
granulocyte	CL:0000094	65.20	gold quality
cerebellum	UBERON:0002037	64.99	gold quality
bone marrow cell	CL:0002092	64.58	silver quality
prefrontal cortex	UBERON:0000451	63.71	gold quality
right lobe of liver	UBERON:0001114	63.14	gold quality
ganglionic eminence	UBERON:0004023	62.42	gold quality
mouth mucosa	UBERON:0003729	62.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	1907.37
E-GEOD-134144	yes	1877.46
E-ANND-3	yes	4.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

31 targeting SYCP3, 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-1297	99.91	73.41	3162
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-3152-3P	99.10	66.35	678
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-550A-3P	98.37	69.61	632
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-1279	97.83	67.50	1898

Literature-anchored findings (GeneRIF, showing 20)

• We suggest that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein via dominant negative interference. (PMID:14643120)
• In contrast to previously reported high frequency of SYCP3 mutations in patients with azoospermia, only polymorphisms are found in the present study (PMID:16213863)
• SYCP3 is expressed in human testis and is restricted to germ cells. Lack of SYCP3 expression in human testis may have a negative effect on spermatogenesis and male fertility. (PMID:16824523)
• No functional SYCP3 exonic SNP was found in infertile Spanish patients with meiosis arrest, suggesting that SYCP3 mutations very likely are not relevant in Spain in genetic susceptibility to meiosis arrest. (PMID:17434513)
• These observations suggest that SCP3 is expressed in adult human and monkey ovaries. (PMID:18256545)
• mutations in SYPR3 are likely to generate an aberrant synaptonemal complex in a dominant-negative manner and contribute to abnormal chromosomal behavior that might lead to recurrent miscarriage. (PMID:19110213)
• X-linked lymphocyte-regulated protein pM1 (XMR), XLR, and SCP3 render tumor cells resistant to antitumor immunity (PMID:20395201)
• mutation analysis of SYCP3, DNMT3L and MSH4 in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages; heterozygous change, detected in a conserved functional domain of the SYCP3 gene, was absent in >200 controls (PMID:21126912)
• The 657T>C mutation of SYCP3 may not be associated with recurrent miscarriage caused by aneuploidy. (PMID:21357605)
• Expression of SYCP3 inhibits the homologous recombination (HR) pathway mediated by RAD51. (PMID:22116401)
• mutations in SYCP3 do not contribute significantly to risk for recurrent miscarriage through maternal meiotic nondisjunction. (PMID:22197129)
• SYCP3 mutations are not associated with the genetic susceptibility for meiotic arrest in infertile male patients with nonobstructive azoospermia in the Turkish population (PMID:22670862)
• Positive synaptonemal complex protein 3 expression is a portent of poor outcome and may be a potential biomarker in the early stages of the non-small cell lung cancer for survival. (PMID:23069255)
• screening for genetic variants in AURKB and SYCP3 among these patients with reproductive problems using Sanger sequencing. Only one apparently non-pathogenic deletion was found in SYCP3. (PMID:23100464)
• SCP3 plays an important role in the progression of cervical cancer (PMID:24905095)
• SYCP3 binding and assembly on meiotic chromosomes leads to their organisation into compact structures compatible with recombination and crossover formation (PMID:24950965)
• The T657C polymorphism of the SYCP3 gene is possibly associated with recurrent pregnancy loss of unknown cause in human. (PMID:25059562)
• In the model, the reported compaction of chromosomal DNA caused by SYCP3 would result from its ability to bridge distant sites on a DNA molecule with the DNA-binding domains located at each end of its strut-like structure. (PMID:28287952)
• SCP3 is associated with lymphangiogenesis and provides insight into the SCP3-VEGF-C/VEGF-D axis based cancer therapy strategy. (PMID:28623914)
• SYCP3 binds to RAD51 and attenuates RAD51 activity during meiosis. (PMID:28745000)

Cross-species orthologs

110 orthologs

Organism	Symbol	Gene ID
danio_rerio	sycp3	ENSDARG00000013438
mus_musculus	Sycp3	ENSMUSG00000020059
mus_musculus	3830403N18Rik	ENSMUSG00000031125
mus_musculus	Xlr	ENSMUSG00000054626
mus_musculus	1700013H16Rik	ENSMUSG00000054727
mus_musculus	Slxl1	ENSMUSG00000067909
mus_musculus	Gm14525	ENSMUSG00000071788
mus_musculus	Gm773	ENSMUSG00000073177
mus_musculus	Gm14819	ENSMUSG00000073245
mus_musculus	Gm10486	ENSMUSG00000073247
mus_musculus	Gm14632	ENSMUSG00000073255
mus_musculus	Gm10488	ENSMUSG00000073257
mus_musculus	Gm1993	ENSMUSG00000073267
mus_musculus	Gm5168	ENSMUSG00000079655
mus_musculus	Gm6121	ENSMUSG00000080725
mus_musculus	Gm4297	ENSMUSG00000081218
mus_musculus	Gm2012	ENSMUSG00000082639
mus_musculus	Gm2030	ENSMUSG00000083628
mus_musculus	Gm5934	ENSMUSG00000084063
mus_musculus	Gm21865	ENSMUSG00000093895
mus_musculus	Gm5935	ENSMUSG00000093923
mus_musculus	Gm20736	ENSMUSG00000093993
mus_musculus	Gm21739	ENSMUSG00000094181
mus_musculus	Gm21477	ENSMUSG00000094399
mus_musculus	Gm20931	ENSMUSG00000094570
mus_musculus	Gm20888	ENSMUSG00000094616
mus_musculus	Gm4836	ENSMUSG00000094624
mus_musculus	Gm21650	ENSMUSG00000094647
mus_musculus	Gm16430	ENSMUSG00000094714
mus_musculus	Gm20916	ENSMUSG00000094746
mus_musculus	Gm10487	ENSMUSG00000094759
mus_musculus	Gm21256	ENSMUSG00000094782
mus_musculus	Gm28490	ENSMUSG00000094789
mus_musculus	Gm21518	ENSMUSG00000094821
mus_musculus	Gm20838	ENSMUSG00000095011
mus_musculus	Slx	ENSMUSG00000095063
mus_musculus	Gm21858	ENSMUSG00000095135
mus_musculus	Gm28891	ENSMUSG00000095141
mus_musculus	Gm21095	ENSMUSG00000095153
mus_musculus	Gm21094	ENSMUSG00000095263
mus_musculus	Gm10058	ENSMUSG00000095293
mus_musculus	Gm10230	ENSMUSG00000095546
mus_musculus	Gm21760	ENSMUSG00000095578
mus_musculus	Gm21258	ENSMUSG00000095606
mus_musculus	Gm20855	ENSMUSG00000095793
mus_musculus	Gm10096	ENSMUSG00000095887
mus_musculus	Gm21209	ENSMUSG00000095979
mus_musculus	Gm20937	ENSMUSG00000096016
mus_musculus	Gm20837	ENSMUSG00000096178
mus_musculus	Gm10147	ENSMUSG00000096457
mus_musculus	Gm16405	ENSMUSG00000096468
mus_musculus	Gm5169	ENSMUSG00000096620
mus_musculus	Gm21861	ENSMUSG00000096626
mus_musculus	Gm20896	ENSMUSG00000096650
mus_musculus	Gm21117	ENSMUSG00000096769
mus_musculus	Gm20843	ENSMUSG00000096902
mus_musculus	Gm20869	ENSMUSG00000099531
mus_musculus	Gm21488	ENSMUSG00000099541
mus_musculus	Gm28897	ENSMUSG00000099740
mus_musculus	Gm20903	ENSMUSG00000099782
mus_musculus	Gm29564	ENSMUSG00000099792
mus_musculus	Gm21409	ENSMUSG00000099840
mus_musculus	Gm20906	ENSMUSG00000099856
mus_musculus	Gm20911	ENSMUSG00000099894
mus_musculus	Gm28827	ENSMUSG00000099925
mus_musculus	Gm20817	ENSMUSG00000100032
mus_musculus	Gm20929	ENSMUSG00000100045
mus_musculus	Gm20890	ENSMUSG00000100055
mus_musculus	Gm29554	ENSMUSG00000100231
mus_musculus	Gm20820	ENSMUSG00000100240
mus_musculus	Gm28870	ENSMUSG00000100338
mus_musculus	Gm29582	ENSMUSG00000100467
mus_musculus	Gm20920	ENSMUSG00000100485
mus_musculus	Gm20870	ENSMUSG00000100535
mus_musculus	Gm21996	ENSMUSG00000100608
mus_musculus	Gm28576	ENSMUSG00000100645
mus_musculus	Gm57478	ENSMUSG00000100667
mus_musculus	Gm21173	ENSMUSG00000100708
mus_musculus	Gm21497	ENSMUSG00000100726
mus_musculus	Gm21627	ENSMUSG00000100856
mus_musculus	Gm20897	ENSMUSG00000100892
mus_musculus	Gm20850	ENSMUSG00000100902
mus_musculus	Gm28998	ENSMUSG00000100939
mus_musculus	Gm28553	ENSMUSG00000100972
mus_musculus	Gm20814	ENSMUSG00000101146
mus_musculus	Sly	ENSMUSG00000101155
mus_musculus	Gm20905	ENSMUSG00000101157
mus_musculus	Gm20894	ENSMUSG00000101158
mus_musculus	Gm28919	ENSMUSG00000101243
mus_musculus	Gm21317	ENSMUSG00000101286
mus_musculus	Gm28510	ENSMUSG00000101396
mus_musculus	Gm28961	ENSMUSG00000101399
mus_musculus	Gm29276	ENSMUSG00000101471
mus_musculus	Gm29110	ENSMUSG00000101528
mus_musculus	Gm20792	ENSMUSG00000101653
mus_musculus	Gm20908	ENSMUSG00000101766
mus_musculus	Gm28102	ENSMUSG00000101915
mus_musculus	Gm20824	ENSMUSG00000101928
mus_musculus	Gm20835	ENSMUSG00000101933
mus_musculus	Gm21294	ENSMUSG00000102045
mus_musculus	Gm20883	ENSMUSG00000102122
mus_musculus	Gm29866	ENSMUSG00000102668
mus_musculus	Gm35134	ENSMUSG00000103371
mus_musculus	Gm31571	ENSMUSG00000103528
mus_musculus	Gm21366	ENSMUSG00000103919
mus_musculus	Gm30737	ENSMUSG00000104191
rattus_norvegicus	Sycp3	ENSRNOG00000005270
rattus_norvegicus	3830403N18Rikl	ENSRNOG00000027907
rattus_norvegicus	Fam9b	ENSRNOG00000037455
rattus_norvegicus	Sycp3l2	ENSRNOG00000051360

Paralogs (3): FAM9B (ENSG00000177138), FAM9A (ENSG00000183304), FAM9C (ENSG00000187268)

Protein

Protein identifiers

Synaptonemal complex protein 3 — Q8IZU3 (reviewed: Q8IZU3)

All UniProt accessions (1): Q8IZU3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase. Required for centromere pairing during meiosis in male germ cells. Required for normal meiosis during spermatogenesis and male fertility. Plays a lesser role in female fertility. Required for efficient phosphorylation of HORMAD1 and HORMAD2.

Subunit / interactions. Component of the lateral elements of synaptonemal complexes. Homotetramer; the tetrameric helix bundles assemble end to end into long homopolimeric fibers that exhibit a transversal striation with a periodicity of about 20 nm (in vitro). Interacts with SYCP2. Forms a complex with EWSR1, PRDM9, REC8 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8.

Subcellular location. Nucleus. Chromosome. Centromere.

Tissue specificity. Testis-specific.

Post-translational modifications. Phosphorylated.

Disease relevance. Spermatogenic failure 4 (SPGF4) [MIM:270960] An infertility disorder characterized by azoospermia, a condition of having no sperm present in the ejaculate. Testicular histology shows arrest of spermatogenesis at the pachytene stage of primary spermatocytes. The disease is caused by variants affecting the gene represented in this entry. Pregnancy loss, recurrent, 4 (RPRGL4) [MIM:270960] A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. Composed of a long central coiled coil domain. The N-terminal and C-terminal regions interact with DNA.

Similarity. Belongs to the XLR/SYCP3 family.

RefSeq proteins (3): NP_001171419, NP_001171420, NP_710161 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006888	XLR/SYCP3/FAM9_dom	Domain
IPR051443	XLR/SYCP3	Family

Pfam: PF04803

UniProt features (17 total): region of interest 5, mutagenesis site 4, modified residue 3, helix 2, chain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4CPC	X-RAY DIFFRACTION	2.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZU3-F1	81.79	0.67

Functional residue map

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

Post-translational modifications (3): 59, 36, 38

Mutagenesis-validated functional residues (4):

Position	Phenotype
52–57	impairs dna binding. abolishes dna binding; when associated with 88-a–a-91.
69–74	abolishes fiber formation.
88–91	impairs dna binding. abolishes dna binding; when associated with 52-a–a-57.
231–236	abolishes fiber formation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1221632	Meiotic synapsis
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 121 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_MEIOTIC_SYNAPSIS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_MALE_GAMETE_GENERATION, GOBP_ORGANELLE_FISSION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, GOBP_NUCLEUS_ORGANIZATION, GOBP_MALE_MEIOSIS_I, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE, GOBP_SPERMATID_NUCLEUS_DIFFERENTIATION, AFFAR_YY1_TARGETS_UP

GO Biological Process (5): male meiosis I (GO:0007141), spermatid development (GO:0007286), sperm DNA condensation (GO:0035092), cell division (GO:0051301), meiotic cell cycle (GO:0051321)

GO Molecular Function (2): DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromosome, centromeric region (GO:0000775), synaptonemal complex (GO:0000795), lateral element (GO:0000800), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiosis I	1
male meiotic nuclear division	1
male gamete generation	1
meiotic cell cycle	1
germ cell development	1
spermatid differentiation	1
chromatin organization	1
spermatid nucleus differentiation	1
cellular process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
nucleic acid binding	1
binding	1
chromosomal region	1
synaptonemal structure	1
synaptonemal complex	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYCP3	SYCP1	Q15431	993
SYCP3	SYCP2	Q9BX26	989
SYCP3	HORMAD2	Q8N7B1	979
SYCP3	HORMAD1	Q86X24	972
SYCP3	MSH4	O15457	946
SYCP3	SYCE2	Q6PIF2	944
SYCP3	TEX12	Q9BXU0	922
SYCP3	FAM9A	Q8IZU1	905
SYCP3	SYCE3	A1L190	902
SYCP3	SYCE1	Q8N0S2	883
SYCP3	STRA8	Q7Z7C7	848
SYCP3	SPO11	Q9Y5K1	844
SYCP3	STAG3	Q9UJ98	834
SYCP3	REC8	O95072	819
SYCP3	DAZL	Q92904	806

IntAct

15 interactions, top by confidence:

A	B	Type	Score
SYCP3	BLK	psi-mi:“MI:0915”(physical association)	0.590
SYCP3	C14orf119	psi-mi:“MI:0915”(physical association)	0.560
SYCP3	NXF1	psi-mi:“MI:0915”(physical association)	0.560
CDC37	SYCP3	psi-mi:“MI:0915”(physical association)	0.560
SYCP3	BRCA2	psi-mi:“MI:0915”(physical association)	0.460
BRCA2	SYCP3	psi-mi:“MI:0403”(colocalization)	0.460
SUMO2	TP53	psi-mi:“MI:0914”(association)	0.350
C14orf119	SYCP3	psi-mi:“MI:0915”(physical association)	0.000
NXF1	SYCP3	psi-mi:“MI:0915”(physical association)	0.000
CDC37	SYCP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): BLK (Affinity Capture-MS), SYCP3 (Affinity Capture-MS), SYCP3 (Two-hybrid), SYCP3 (Affinity Capture-Western), SYCP3 (Affinity Capture-Western), SYCP3 (Affinity Capture-Western), BRCA1 (Co-localization), ATR (Co-localization), MDC1 (Co-localization), SYCP3 (Co-localization), SYCP3 (Two-hybrid), NXF1 (Two-hybrid), C14orf119 (Two-hybrid), SYCP3 (Co-localization), BLK (Affinity Capture-MS)

ESM2 similar proteins: A1L3H4, A5A777, A6H754, A7YY97, A9ULR1, B2GV52, C7GUN6, D3ZNV2, P05531, P0CAP1, P33716, P57679, P70281, Q03954, Q0IHJ3, Q28HY7, Q32L59, Q3UIJ9, Q4R764, Q4V9P3, Q58CS6, Q5EB94, Q5I0J4, Q5RA87, Q5XIC3, Q5ZK77, Q60547, Q60595, Q61806, Q63520, Q640Z7, Q6AY08, Q6CQ94, Q6NPG7, Q6P205, Q7L3B6, Q80Y56, Q810N9, Q8BXX9, Q8GYM3

Diamond homologs: P05531, P70281, Q3T0E2, Q4R764, Q60547, Q63520, Q8IZU3, Q60595, Q61806, Q6P205, Q8IZU0, Q8IZT9, Q8IZU1, Q9JJR2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SYCP3	“form complex”	Synaptonemal_complex	binding
RAD51	“up-regulates activity”	SYCP3	binding
DMC1	“up-regulates activity”	SYCP3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	36
Likely benign	2
Benign	14

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
5371	NM_001177949.2(SYCP3):c.643del (p.Ile215fs)	Pathogenic
5372	NM_001177949.2(SYCP3):c.553-21_553-18del	Pathogenic
5373	NM_001177949.2(SYCP3):c.657T>C (p.Thr219=)	Pathogenic

SpliceAI

1550 predictions. Top by Δscore:

Variant	Effect	Δscore
12:101728987:CA:C	acceptor_gain	1.0000
12:101728988:A:C	acceptor_gain	1.0000
12:101729209:ATACT:A	acceptor_gain	1.0000
12:101729210:TACT:T	acceptor_gain	1.0000
12:101729212:CT:C	acceptor_gain	1.0000
12:101729214:C:CC	acceptor_gain	1.0000
12:101729214:CT:C	acceptor_loss	1.0000
12:101731588:A:C	donor_gain	1.0000
12:101731662:ATATT:A	acceptor_gain	1.0000
12:101731663:TATT:T	acceptor_gain	1.0000
12:101731664:ATTC:A	acceptor_loss	1.0000
12:101731665:TT:T	acceptor_gain	1.0000
12:101731665:TTCTA:T	acceptor_loss	1.0000
12:101731666:TC:T	acceptor_loss	1.0000
12:101731667:C:CC	acceptor_gain	1.0000
12:101733588:T:TA	donor_gain	1.0000
12:101734921:CCTTA:C	donor_loss	1.0000
12:101734922:CTTA:C	donor_loss	1.0000
12:101734923:TTA:T	donor_loss	1.0000
12:101734924:TACCT:T	donor_loss	1.0000
12:101734925:A:AC	donor_gain	1.0000
12:101734925:A:C	donor_loss	1.0000
12:101734926:C:CC	donor_gain	1.0000
12:101734926:CCTT:C	donor_loss	1.0000
12:101735040:GTCAA:G	acceptor_gain	1.0000
12:101735041:TCAA:T	acceptor_gain	1.0000
12:101735042:CAA:C	acceptor_gain	1.0000
12:101735042:CAAC:C	acceptor_gain	1.0000
12:101735043:AA:A	acceptor_gain	1.0000
12:101735043:AAC:A	acceptor_loss	1.0000

AlphaMissense

1594 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:101733622:A:G	W136R	0.991
12:101733622:A:T	W136R	0.991
12:101728955:C:G	R228P	0.988
12:101728946:A:G	L231P	0.979
12:101728950:A:G	S230P	0.977
12:101728958:A:T	V227D	0.976
12:101728946:A:T	L231H	0.973
12:101735016:C:A	K88N	0.972
12:101735016:C:G	K88N	0.972
12:101728965:C:G	A225P	0.970
12:101728930:G:C	F236L	0.965
12:101728930:G:T	F236L	0.965
12:101728932:A:G	F236L	0.965
12:101734985:A:G	S99P	0.965
12:101733666:A:G	L121P	0.964
12:101735005:A:G	L92P	0.964
12:101728941:A:G	S233P	0.962
12:101734971:A:C	S103R	0.962
12:101734971:A:T	S103R	0.962
12:101734973:T:G	S103R	0.962
12:101729141:C:G	A209P	0.958
12:101735026:A:G	L85P	0.958
12:101731650:T:G	Q157P	0.957
12:101733674:C:A	R118S	0.956
12:101733674:C:G	R118S	0.956
12:101734981:A:G	L100P	0.956
12:101731630:A:G	S164P	0.955
12:101731647:T:G	Q158P	0.955
12:101728973:T:G	Q222P	0.948
12:101733652:A:G	S126P	0.947

dbSNP variants (sampled 300 via entrez): RS1000066982 (12:101732749 C>T), RS1000187393 (12:101733047 A>C), RS1000280732 (12:101732661 C>G,T), RS1000561224 (12:101734247 T>C), RS1000572016 (12:101740279 A>G), RS1000621299 (12:101732663 TTTTTC>T), RS1000734637 (12:101740308 T>A), RS1001264387 (12:101728585 C>T), RS1001542758 (12:101731918 A>G), RS1001736574 (12:101728182 G>A), RS1001745945 (12:101730474 T>A,C), RS1001856978 (12:101739862 A>G), RS1001971727 (12:101738774 C>A), RS1002270109 (12:101730429 T>C,G), RS1002276314 (12:101740158 C>A)

Disease associations

OMIM: gene MIM:604759 | disease phenotypes: MIM:270960

GenCC curated gene-disease

Disease	Classification	Inheritance
infertility disorder	Moderate	Autosomal dominant
spermatogenic failure 4	Limited	Autosomal dominant

Mondo (3): spermatogenic failure 4 (MONDO:0010052), male infertility (MONDO:0005372), infertility disorder (MONDO:0005047)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000837	Increased circulating gonadotropin level
HP:0003251	Male infertility
HP:0008669	Abnormal spermatogenesis
HP:0008734	Decreased testicular size
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0011962	Obstructive azoospermia
HP:0200067	Recurrent spontaneous abortion

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_2	Brain morphology (MOSTest)	3.000000e-37

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007246	Infertility	C12.100.750
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
C536875	Arrest of spermatogenesis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
jinfukang	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Cisplatin	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Nickel	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT04701034	PHASE2	COMPLETED	Intravenous Immunoglobulin and Prednisolone for RPL After ART.
NCT04850261	PHASE2	WITHDRAWN	Injection Free IVF
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01330771	Not specified	COMPLETED	Assessment of the Therapeutic Utility of r-FSH in Association With hMG-HP
NCT01330784	Not specified	COMPLETED	Assessment of the Therapeutic Utility of hMG-HP
NCT01331720	Not specified	COMPLETED	Assessment of the Effectiveness and Tolerability of Ovarian Hyperstimulation
NCT01331733	Not specified	COMPLETED	Comparative Assessment of the Clinical Utility of Ovarian Stimulation With Menotropin Versus Menotropin Plus GnRH Antagonist