SUN5

Summary

SUN5 (Sad1 and UNC84 domain containing 5, HGNC:16252) is a protein-coding gene on chromosome 20q11.21, encoding SUN domain-containing protein 5 (Q8TC36). Plays an essential role in anchoring sperm head to the tail.

The protein encoded by this gene appears to play a role in the meiotic stage of spermatogenesis. The encoded protein localizes to the junction between the sperm head and body and may be involved in nuclear envelope reconstitution and nuclear migration. Mutations in this gene have been implicated in acephalic spermatozoa syndrome.

Source: NCBI Gene 140732 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 16 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 70 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_080675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16252
Approved symbol	SUN5
Name	Sad1 and UNC84 domain containing 5
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	dJ726C3.1, TSARG4
Ensembl gene	ENSG00000167098
Ensembl biotype	protein_coding
OMIM	613942
Entrez	140732

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000356173, ENST00000375519, ENST00000375523, ENST00000420875

RefSeq mRNA: 1 — MANE Select: NM_080675 NM_080675

CCDS: CCDS13209

Canonical transcript exons

ENST00000356173 — 13 exons

Exon	Start	End
ENSE00001109603	32985099	32985185
ENSE00001109609	32985736	32985903
ENSE00001109610	32987660	32987775
ENSE00001154023	33002587	33002661
ENSE00001154030	33002861	33002919
ENSE00001154036	33000074	33000135
ENSE00001180080	32989620	32989698
ENSE00001180087	32995619	32995727
ENSE00001180096	32996324	32996358
ENSE00001180104	32997638	32997687
ENSE00001180118	33001212	33001278
ENSE00001180143	33004264	33004433
ENSE00003847632	32983775	32983949

Expression profiles

Bgee: expression breadth broad, 28 present calls, max score 91.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0514 / max 53.6791, expressed in 3 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186946	0.0454	3
186945	0.0060	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	91.16	gold quality
left testis	UBERON:0004533	90.78	gold quality
testis	UBERON:0000473	87.68	gold quality
upper arm skin	UBERON:0004263	86.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	83.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.66	silver quality
left ventricle myocardium	UBERON:0006566	81.62	gold quality
kidney epithelium	UBERON:0004819	77.73	gold quality
nasal cavity epithelium	UBERON:0005384	76.95	gold quality
secondary oocyte	CL:0000655	76.76	silver quality
mucosa of paranasal sinus	UBERON:0005030	76.64	gold quality
cerebellar vermis	UBERON:0004720	76.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.95	gold quality
myocardium	UBERON:0002349	75.93	gold quality
epithelial cell of pancreas	CL:0000083	75.92	gold quality
amniotic fluid	UBERON:0000173	75.03	silver quality
quadriceps femoris	UBERON:0001377	74.77	gold quality
sperm	CL:0000019	74.09	silver quality
vastus lateralis	UBERON:0001379	74.09	gold quality
tibialis anterior	UBERON:0001385	73.91	silver quality
deltoid	UBERON:0001476	72.99	gold quality
endothelial cell	CL:0000115	71.81	silver quality
layer of synovial tissue	UBERON:0007616	71.60	silver quality
epithelium of nasopharynx	UBERON:0001951	71.59	gold quality
thymus	UBERON:0002370	71.51	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.27	gold quality
pancreatic ductal cell	CL:0002079	70.25	silver quality
biceps brachii	UBERON:0001507	70.16	gold quality
adult organism	UBERON:0007023	70.05	gold quality
lateral globus pallidus	UBERON:0002476	69.82	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.46

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• SPAG4L may play an important role in the meiotic stage of spermatogenesis (PMID:21711156)
• results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome (PMID:27640305)
• Results, together with those of the previous study, show that SUN5 is required for the formation of the sperm head-tail junction and male fertility. (PMID:28541472)
• A new SUN5 mutation (c.475C–>T; p.Arg159*) impair its interaction with DNAJB13. (PMID:29298896)
• The contribution of SUN5 mutations to acephalic spermatozoa might not be as high as described previously. (PMID:29331481)
• Novel mutations in PMFBP1, TSGA10 and SUN5: Expanding the spectrum of mutations that may cause acephalic spermatozoa. (PMID:32285443)
• Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa. (PMID:33671757)
• Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome. (PMID:34159570)
• SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction. (PMID:38870534)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sun5	ENSMUSG00000027480
rattus_norvegicus	Sun5	ENSRNOG00000027221
caenorhabditis_elegans		WBGENE00006816

Paralogs (4): SPAG4 (ENSG00000061656), SUN2 (ENSG00000100242), SUN3 (ENSG00000164744), SUN1 (ENSG00000164828)

Protein

Protein identifiers

SUN domain-containing protein 5 — Q8TC36 (reviewed: Q8TC36)

Alternative names: Sad1 and UNC84 domain-containing protein 5, Sperm-associated antigen 4-like protein, Testis and spermatogenesis-related gene 4 protein

All UniProt accessions (5): A0A384MDU5, A9Z1W8, Q8TC36, Q5TDX8, Q5TDX9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in anchoring sperm head to the tail. Is responsible for the attachment of the coupling apparatus to the sperm nuclear envelope.

Subunit / interactions. Probable homotrimer. Interacts with DNAJB13.

Subcellular location. Nucleus inner membrane. Golgi apparatus.

Tissue specificity. Sperm (at protein level). Widely expressed. Conflictingly shown to be specifically expressed in testis.

Post-translational modifications. Highly glycosylated in the Golgi apparatus during spermiogenesis.

Disease relevance. Spermatogenic failure 16 (SPGF16) [MIM:617187] An infertility disorder caused by spermatogenesis defects and characterized by abnormally shaped spermatozoa in the semen of affected individuals. Most spermatozoa are made up of headless tails, while a small proportion has an abnormal head-tail junction. A few spermatozoa are made up of tailless heads. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_542406* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012919	SUN_dom	Domain
IPR045119	SUN1-5	Family

Pfam: PF07738

UniProt features (20 total): sequence variant 12, topological domain 2, chain 1, transmembrane region 1, domain 1, region of interest 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TC36-F1	75.31	0.42

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, DBP_Q6, chr20q11, GOCC_NUCLEAR_ENVELOPE, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_NUCLEAR_INNER_MEMBRANE, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_NUCLEAR_MEMBRANE, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, TEF_Q6, GOCC_ORGANELLE_ENVELOPE, MARTENS_TRETINOIN_RESPONSE_UP

GO Biological Process (3): spermatogenesis (GO:0007283), spermatid development (GO:0007286), cell differentiation (GO:0030154)

GO Molecular Function (2): protein-membrane adaptor activity (GO:0043495), protein binding (GO:0005515)

GO Cellular Component (7): nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), Golgi apparatus (GO:0005794), meiotic nuclear membrane microtubule tethering complex (GO:0034993), sperm head-tail coupling apparatus (GO:0120212), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
developmental process involved in reproduction	1
male gamete generation	1
germ cell development	1
spermatid differentiation	1
cellular developmental process	1
protein-macromolecule adaptor activity	1
binding	1
nucleus	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
cytoplasm	1
microtubule organizing center attachment site	1
nuclear membrane microtubule tethering complex	1

Protein interactions and networks

STRING

1098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUN5	PMFBP1	Q8TBY8	796
SUN5	SPATA6	Q9NWH7	749
SUN5	ODF1	Q14990	735
SUN5	TSGA10	Q9BZW7	691
SUN5	SYNE1	Q8NF91	686
SUN5	DPY19L2	Q6NUT2	684
SUN5	HOOK1	Q9UJC3	681
SUN5	KASH5	Q8N6L0	596
SUN5	SYNE4	Q8N205	583
SUN5	CEP112	Q8N8E3	571
SUN5	DNAJB13	P59910	567
SUN5	BRDT	Q58F21	557
SUN5	CCDC42	Q96M95	552
SUN5	SYNE3	Q6ZMZ3	545
SUN5	SPATC1L	Q9H0A9	531

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SUN5	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
SUN5	KLHL36	psi-mi:“MI:0915”(physical association)	0.400
SUN5	SPAG4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): SUN5 (Two-hybrid), KLHL36 (Affinity Capture-MS), TTC4 (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex), SUN5 (Reconstituted Complex)

ESM2 similar proteins: A1L3I3, A2CI98, D3ZF92, O43278, O55034, O75509, O88393, O94901, P0C6P5, P35054, P59729, P98153, P98154, Q0II64, Q0VCT2, Q2KHT9, Q5BIR3, Q5HZE8, Q5PQS0, Q5RD34, Q5VUB5, Q61003, Q6AXX1, Q6DGF9, Q7TNI2, Q7TSI1, Q7Z2W4, Q80U38, Q8BJN4, Q8BJS4, Q8BZN4, Q8C2B3, Q8IUY3, Q8TAQ9, Q8TC36, Q8WUI4, Q8WYL5, Q91ZV2, Q91ZV3, Q95LV7

Diamond homologs: A0A0B4KEE4, O55034, O94901, Q09825, Q0II64, Q20745, Q5SS91, Q8BJS4, Q8TAQ9, Q8TC36, Q95LV7, Q9D666, Q9DA32, Q9JJF2, Q9NPE6, Q9UH99, Q9SG79, Q558Z2, Q9FF75

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SUN5	“form complex”	“LINC complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	55
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
268047	NM_080675.4(SUN5):c.824C>T (p.Thr275Met)	Pathogenic
268049	NM_080675.4(SUN5):c.485T>A (p.Met162Lys)	Pathogenic
268051	NM_080675.4(SUN5):c.781G>A (p.Val261Met)	Pathogenic
268052	NM_080675.4(SUN5):c.851C>G (p.Ser284Ter)	Pathogenic
3248297	NC_000020.10:g.(?31571600)(33001705_?)del	Pathogenic
268048	NM_080675.4(SUN5):c.1066C>T (p.Arg356Cys)	Likely pathogenic
4077674	NM_080675.4(SUN5):c.445C>T (p.Arg149Ter)	Likely pathogenic
4845882	NM_080675.4(SUN5):c.211+1_211+2dupGT	Likely pathogenic

SpliceAI

1793 predictions. Top by Δscore:

Variant	Effect	Δscore
20:32985716:C:CA	donor_gain	1.0000
20:32985734:A:AC	donor_gain	1.0000
20:32985735:C:CC	donor_gain	1.0000
20:32989694:TTTTG:T	acceptor_gain	1.0000
20:32989696:TTG:T	acceptor_gain	1.0000
20:32989696:TTGC:T	acceptor_loss	1.0000
20:32989697:TG:T	acceptor_gain	1.0000
20:32989697:TGCTG:T	acceptor_loss	1.0000
20:32989699:C:CC	acceptor_gain	1.0000
20:32989699:C:T	acceptor_loss	1.0000
20:32989700:T:A	acceptor_loss	1.0000
20:32995734:A:T	acceptor_gain	1.0000
20:32985195:C:CT	acceptor_gain	0.9900
20:32985712:AGCTC:A	donor_gain	0.9900
20:32985904:C:CC	acceptor_gain	0.9900
20:32987673:T:TA	donor_gain	0.9900
20:32989615:CCTA:C	donor_loss	0.9900
20:32989616:CTA:C	donor_loss	0.9900
20:32989617:TAC:T	donor_loss	0.9900
20:32989618:A:AC	donor_gain	0.9900
20:32989619:C:CC	donor_gain	0.9900
20:32989619:C:CT	donor_loss	0.9900
20:32989695:TTTG:T	acceptor_gain	0.9900
20:32995613:TCTCA:T	donor_loss	0.9900
20:32995614:CTCAC:C	donor_loss	0.9900
20:32995615:TCA:T	donor_loss	0.9900
20:32995616:CA:C	donor_loss	0.9900
20:32995618:C:CG	donor_loss	0.9900
20:32995727:CC:C	acceptor_loss	0.9900
20:32995728:CTT:C	acceptor_loss	0.9900

AlphaMissense

2524 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:32985877:C:A	W252C	0.999
20:32985877:C:G	W252C	0.999
20:32985879:A:G	W252R	0.999
20:32985879:A:T	W252R	0.999
20:32983867:C:G	R356P	0.998
20:32983861:C:G	R358P	0.997
20:32983921:A:T	V338D	0.997
20:32985755:G:T	P293H	0.997
20:32985845:A:T	I263N	0.997
20:32989631:A:G	L201P	0.997
20:32989634:G:T	A200D	0.997
20:32985149:C:A	G312W	0.996
20:32985878:C:G	W252S	0.996
20:32989636:A:C	F199L	0.996
20:32989636:A:T	F199L	0.996
20:32989638:A:G	F199L	0.996
20:32985135:A:C	F316L	0.995
20:32985135:A:T	F316L	0.995
20:32985136:A:G	F316S	0.995
20:32985137:A:G	F316L	0.995
20:32985806:A:G	L276P	0.995
20:32985845:A:C	I263S	0.995
20:32985845:A:G	I263T	0.995
20:32987664:A:T	L242H	0.995
20:32985108:G:C	F325L	0.994
20:32985108:G:T	F325L	0.994
20:32985110:A:G	F325L	0.994
20:32985141:A:C	F314L	0.994
20:32985141:A:T	F314L	0.994
20:32985143:A:G	F314L	0.994

dbSNP variants (sampled 300 via entrez): RS1000030433 (20:32992336 G>T), RS1000146228 (20:32992045 T>G), RS1000182377 (20:32991780 CTT>C,CTTTT), RS1000483645 (20:33004051 G>A), RS1000640810 (20:33006382 A>T), RS1000771374 (20:33002764 G>A,T), RS1000786055 (20:32984127 A>G), RS1000859737 (20:32984399 G>T), RS1001523123 (20:32987138 C>T), RS1001590839 (20:32993061 A>G), RS1001786685 (20:32985495 T>C), RS1002267561 (20:32988000 C>A), RS1002460883 (20:32988126 G>A), RS1002535872 (20:32988269 G>T), RS1002658904 (20:33002923 G>A,C)

Disease associations

OMIM: gene MIM:613942 | disease phenotypes: MIM:617187, MIM:613752

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 16	Strong	Autosomal recessive

Mondo (2): spermatogenic failure 16 (MONDO:0014961), hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (MONDO:0013404)

Orphanet (1): S-adenosylhomocysteine hydrolase deficiency (Orphanet:88618)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000798	Oligozoospermia
HP:0002916	Abnormality of chromosome segregation
HP:0003251	Male infertility
HP:0008226	Androgen insufficiency
HP:0011462	Young adult onset
HP:0012207	Reduced sperm motility
HP:0012867	Abnormal sperm mid-piece morphology
HP:0012869	Acephalic spermatozoa

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009724_102	Vertical cup-disc ratio (multi-trait analysis)	4.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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