FSIP2

Summary

FSIP2 (fibrous sheath interacting protein 2, HGNC:21675) is a protein-coding gene on chromosome 2q32.1, encoding Fibrous sheath-interacting protein 2 (Q5CZC0). Plays a role in spermatogenesis.

This gene encodes a protein associated with the sperm fibrous sheath. Genes encoding most of the fibrous-sheath associated proteins genes are transcribed only during the postmeiotic period of spermatogenesis. The protein encoded by this gene is specific to spermatogenic cells. Copy number variation in this gene may be associated with testicular germ cell tumors. Pseudogenes associated with this gene are reported on chromosomes 2 and X.

Source: NCBI Gene 401024 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 34 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 1,179 total — 14 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_173651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21675
Approved symbol	FSIP2
Name	fibrous sheath interacting protein 2
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34780
Ensembl gene	ENSG00000188738
Ensembl biotype	protein_coding
OMIM	615796
Entrez	401024

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 nonsense_mediated_decay, 1 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000415915, ENST00000424728, ENST00000429412, ENST00000465275, ENST00000469367

RefSeq mRNA: 1 — MANE Select: NM_173651 NM_173651

CCDS: CCDS54426

Canonical transcript exons

ENST00000424728 — 23 exons

Exon	Start	End
ENSE00001249500	185747313	185747423
ENSE00001249511	185753722	185753842
ENSE00001249518	185746669	185746810
ENSE00001465129	185799697	185809133
ENSE00001465136	185786252	185786288
ENSE00001465137	185782705	185782762
ENSE00001465138	185764502	185764565
ENSE00001465139	185756192	185756278
ENSE00001608504	185739346	185739471
ENSE00001620137	185833090	185833290
ENSE00001673712	185788643	185797526
ENSE00001789173	185738804	185738993
ENSE00001790305	185745429	185745568
ENSE00001799718	185744322	185744411
ENSE00003497958	185761972	185762017
ENSE00003554460	185824434	185824480
ENSE00003608538	185815371	185815471
ENSE00003618926	185763183	185763289
ENSE00003634910	185760988	185761103
ENSE00003652109	185828156	185828199
ENSE00003658264	185813545	185814042
ENSE00003672137	185831813	185831882
ENSE00003677121	185743133	185743294

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 89.29.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1897 / max 40.5830, expressed in 42 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24093	0.1144	26
24089	0.0261	6
24092	0.0149	9
24088	0.0137	4
24090	0.0123	4
24091	0.0054	3
24087	0.0029	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	89.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.88	gold quality
left testis	UBERON:0004533	85.83	gold quality
right testis	UBERON:0004534	85.27	gold quality
testis	UBERON:0000473	83.84	gold quality
mucosa of transverse colon	UBERON:0004991	76.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.36	gold quality
colonic epithelium	UBERON:0000397	75.48	gold quality
calcaneal tendon	UBERON:0003701	73.75	gold quality
transverse colon	UBERON:0001157	71.80	gold quality
adult organism	UBERON:0007023	70.30	gold quality
adrenal tissue	UBERON:0018303	68.77	gold quality
bone marrow cell	CL:0002092	67.96	silver quality
rectum	UBERON:0001052	66.54	gold quality
body of stomach	UBERON:0001161	65.89	gold quality
stomach	UBERON:0000945	65.17	gold quality
sural nerve	UBERON:0015488	65.09	gold quality
right uterine tube	UBERON:0001302	63.73	gold quality
cortical plate	UBERON:0005343	63.29	gold quality
mucosa of stomach	UBERON:0001199	62.45	gold quality
tendon	UBERON:0000043	61.10	gold quality
corpus callosum	UBERON:0002336	61.03	gold quality
adenohypophysis	UBERON:0002196	60.81	gold quality
ganglionic eminence	UBERON:0004023	60.72	gold quality
ventricular zone	UBERON:0003053	60.34	gold quality
colon	UBERON:0001155	60.30	gold quality
pituitary gland	UBERON:0000007	59.74	gold quality
large intestine	UBERON:0000059	59.70	gold quality
left ovary	UBERON:0002119	59.04	gold quality
intestine	UBERON:0000160	58.97	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.51
E-CURD-112	yes	3.67
E-MTAB-7249	no	199.33
E-MTAB-5061	no	3.08
E-MTAB-9801	no	2.82

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• Homozygous loss-of-function mutations in FSIP2 cause male infertility with asthenoteratospermia (PMID:30745215)
• FSIP2 can serve as a predictive biomarker for Clear Cell Renal Cell Carcinoma prognosis. (PMID:33162809)
• Novel mutations in FSIP2 lead to multiple morphological abnormalities of the sperm flagella and poor ICSI prognosis. (PMID:33631238)
• FSIP2 plays a role in the acrosome development during spermiogenesis. (PMID:35654582)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fsip2	ENSMUSG00000075249
rattus_norvegicus	Fsip2	ENSRNOG00000051199

Protein

Protein identifiers

Fibrous sheath-interacting protein 2 — Q5CZC0 (reviewed: Q5CZC0)

All UniProt accessions (3): H0Y515, H7BZL6, Q5CZC0

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in spermatogenesis.

Subunit / interactions. May interact with AKAP4.

Tissue specificity. Predominantly expressed in testis.

Disease relevance. Spermatogenic failure 34 (SPGF34) [MIM:618153] An autosomal recessive infertility disorder caused by spermatogenesis defects that result in multiple abnormalities of sperm flagellum, including irregular-caliber, short, coiled, or absent flagella. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5CZC0-1	1	yes
Q5CZC0-2	2

RefSeq proteins (1): NP_775922* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031554	FSIP2_C	Domain
IPR038891	FSIP2	Family

Pfam: PF15783

UniProt features (49 total): sequence conflict 26, region of interest 9, compositionally biased region 6, sequence variant 3, splice variant 2, chain 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q5CZC0 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (1): 430

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 90 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, AAAYRNCTG_UNKNOWN, CEBPB_01, SOX9_B1, TGCTGAY_UNKNOWN, GOBP_CILIUM_ORGANIZATION, GATA6_01, GOBP_CILIUM_MOVEMENT, WTGAAAT_UNKNOWN, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, OCT1_06, GOBP_ORGANELLE_ASSEMBLY, TGANTCA_AP1_C

GO Biological Process (3): sperm axoneme assembly (GO:0007288), flagellated sperm motility (GO:0030317), protein localization to cilium (GO:0061512)

GO Molecular Function (0):

GO Cellular Component (4): sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), sperm head-tail coupling apparatus (GO:0120212)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
sperm flagellum	3
developmental process involved in reproduction	1
axoneme assembly	1
sperm flagellum assembly	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
protein localization to organelle	1

Protein interactions and networks

STRING

1468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSIP2	AKAP4	Q5JQC9	751
FSIP2	TTC21A	Q8NDW8	687
FSIP2	CFAP43	Q8NDM7	682
FSIP2	DNAH1	Q9P2D7	655
FSIP2	CFAP44	Q96MT7	641
FSIP2	CFAP69	A5D8W1	640
FSIP2	CFAP251	Q8TBY9	624
FSIP2	TTC29	Q8NA56	615
FSIP2	SPEF2	Q9C093	603
FSIP2	ARMC2	Q8NEN0	601
FSIP2	QRICH2	Q9H0J4	600
FSIP2	CFAP91	Q7Z4T9	582
FSIP2	CFAP70	Q5T0N1	570
FSIP2	AKAP3	O75969	532
FSIP2	AK7	Q96M32	519

IntAct

8 interactions, top by confidence:

A	B	Type	Score
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
FSIP2	CANX	psi-mi:“MI:0915”(physical association)	0.400
FSIP2	RPL7L1	psi-mi:“MI:0915”(physical association)	0.400
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
NXT2	MYO1G	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A087WRU1, A0JNH1, A2RUB1, A6QNQ6, B0S6S9, B1WC58, D3Z987, D3ZJ47, E1BC15, O60673, P28358, P28359, P56716, P70347, Q0P5X5, Q0VAV2, Q0VBV7, Q15468, Q2M2Z5, Q3UXL4, Q3V089, Q49A88, Q569L8, Q5BQN8, Q5CZC0, Q5QGS0, Q5T1N1, Q5VWN6, Q60988, Q61493, Q62924, Q6ZP01, Q6ZU52, Q6ZVD7, Q80U59, Q80WQ8, Q86WS4, Q86YC2, Q8CB14, Q8IUR6

Diamond homologs: A2ARZ3, Q5CZC0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1179 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	8
Uncertain significance	919
Likely benign	156
Benign	62

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
2577472	NM_173651.4(FSIP2):c.19981C>T (p.Arg6661Ter)	Pathogenic
2577473	NM_173651.4(FSIP2):c.18448G>A (p.Val6150Ile)	Pathogenic
2577474	NM_173651.4(FSIP2):c.5237AAG[1] (p.Glu1747del)	Pathogenic
2577475	NM_173651.4(FSIP2):c.5480A>T (p.Asp1827Val)	Pathogenic
2577476	NM_173651.4(FSIP2):c.9056T>C (p.Ile3019Thr)	Pathogenic
2577478	NM_173651.4(FSIP2):c.10823T>C (p.Leu3608Ser)	Pathogenic
3239649	NM_173651.4(FSIP2):c.2689del (p.Ser897fs)	Pathogenic
3356032	NM_173651.4(FSIP2):c.8003C>A (p.Ser2668Ter)	Pathogenic
3383076	NM_173651.4(FSIP2):c.6060del (p.Glu2021fs)	Pathogenic
4681487	NM_173651.4(FSIP2):c.17848_17851del (p.Thr5950fs)	Pathogenic
586970	NM_173651.4(FSIP2):c.1607_1616delinsTGT (p.Lys536fs)	Pathogenic
586971	NM_173651.4(FSIP2):c.16393_16396del (p.Asn5465fs)	Pathogenic
586972	NM_173651.4(FSIP2):c.910del (p.Gln304fs)	Pathogenic
586973	NM_173651.4(FSIP2):c.2282dup (p.Asn761fs)	Pathogenic
1335429	NM_173651.4(FSIP2):c.9557del (p.Thr3186fs)	Likely pathogenic
1709916	NM_173651.4(FSIP2):c.1041_1050del (p.Val346_Tyr347insTer)	Likely pathogenic
2577477	NM_173651.4(FSIP2):c.17798C>T (p.Ser5933Phe)	Likely pathogenic
3065719	NM_173651.4(FSIP2):c.2680_2693del (p.Asn894fs)	Likely pathogenic
3352098	NM_173651.4(FSIP2):c.15982del (p.Ile5328fs)	Likely pathogenic
3892645	NM_173651.4(FSIP2):c.14299A>T (p.Arg4767Ter)	Likely pathogenic
3892650	NM_173651.4(FSIP2):c.18220C>T (p.Gln6074Ter)	Likely pathogenic
4845774	NM_173651.4(FSIP2):c.6313dup (p.Thr2105fs)	Likely pathogenic

SpliceAI

3545 predictions. Top by Δscore:

Variant	Effect	Δscore
2:185738989:GAGAC:G	donor_gain	1.0000
2:185738991:GAC:G	donor_gain	1.0000
2:185741682:A:T	donor_gain	1.0000
2:185743295:G:GG	donor_gain	1.0000
2:185744412:G:GG	donor_gain	1.0000
2:185746668:GAT:G	acceptor_gain	1.0000
2:185746808:GAG:G	donor_gain	1.0000
2:185747420:G:GT	donor_gain	1.0000
2:185747421:A:T	donor_gain	1.0000
2:185753874:C:CG	donor_gain	1.0000
2:185753874:C:G	donor_gain	1.0000
2:185761955:A:AG	acceptor_gain	1.0000
2:185761955:AATGT:A	acceptor_gain	1.0000
2:185761956:ATGT:A	acceptor_gain	1.0000
2:185761957:T:G	acceptor_gain	1.0000
2:185761959:T:TA	acceptor_gain	1.0000
2:185764482:T:TA	acceptor_gain	1.0000
2:185764485:T:TA	acceptor_gain	1.0000
2:185764490:T:TA	acceptor_gain	1.0000
2:185786289:G:GG	donor_gain	1.0000
2:185828145:A:AG	acceptor_gain	1.0000
2:185831811:A:AG	acceptor_gain	1.0000
2:185831812:G:GG	acceptor_gain	1.0000
2:185831812:GTTT:G	acceptor_gain	1.0000
2:185738994:G:GG	donor_gain	0.9900
2:185743127:TTGCA:T	acceptor_loss	0.9900
2:185743128:TGCA:T	acceptor_loss	0.9900
2:185743129:GCAGC:G	acceptor_loss	0.9900
2:185743130:CA:C	acceptor_loss	0.9900
2:185743131:A:AG	acceptor_gain	0.9900

AlphaMissense

45961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:185743154:T:C	F83L	0.997
2:185743156:T:A	F83L	0.997
2:185743156:T:G	F83L	0.997
2:185743260:T:C	L118S	0.995
2:185744365:T:C	L144P	0.995
2:185813563:T:C	F6616L	0.995
2:185813565:T:A	F6616L	0.995
2:185813565:T:G	F6616L	0.995
2:185743221:T:C	L105S	0.993
2:185744328:T:C	C132R	0.993
2:185743155:T:C	F83S	0.992
2:185743212:A:G	D102G	0.991
2:185744330:T:G	C132W	0.991
2:185743196:T:C	Y97H	0.989
2:185813633:T:C	L6639P	0.989
2:185743167:A:G	D87G	0.988
2:185744357:G:C	R141S	0.987
2:185744357:G:T	R141S	0.987
2:185743196:T:G	Y97D	0.986
2:185795919:T:C	L2928P	0.985
2:185813606:T:C	L6630S	0.985
2:185744352:T:G	Y140D	0.984
2:185797124:G:C	A3330P	0.984
2:185809016:A:C	R6570S	0.984
2:185809016:A:T	R6570S	0.984
2:185813564:T:C	F6616S	0.983
2:185743202:A:C	S99R	0.982
2:185743204:C:A	S99R	0.982
2:185743204:C:G	S99R	0.982
2:185743239:G:C	R111P	0.982

dbSNP variants (sampled 300 via entrez): RS1000018227 (2:185797432 T>C), RS1000200184 (2:185761960 G>A,C,T), RS1000278024 (2:185757031 T>G), RS1000308018 (2:185832404 T>C), RS1000318288 (2:185742359 T>G), RS1000369159 (2:185815715 CT>C), RS1000381180 (2:185832164 A>G), RS1000429407 (2:185782416 G>C), RS1000432424 (2:185745124 T>A), RS1000443725 (2:185735954 C>A,G), RS1000449429 (2:185800420 A>ATTTATT), RS1000471605 (2:185735712 T>C), RS1000530695 (2:185791980 A>G), RS1000541487 (2:185744889 G>A), RS1000582849 (2:185791614 C>A,T)

Disease associations

OMIM: gene MIM:615796 | disease phenotypes: MIM:618153

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 34	Strong	Autosomal recessive
non-syndromic male infertility due to sperm motility disorder	Supportive	Autosomal recessive

Mondo (3): spermatogenic failure 34 (MONDO:0029148), oligospermia (MONDO:0001913), (MONDO:0017173)

Orphanet (0):

HPO phenotypes

9 total (10 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0012207	Reduced sperm motility
HP:0032558	Absent sperm flagella
HP:0032559	Short sperm flagella
HP:0032560	Coiled sperm flagella
HP:0033393	Irregularly shaped sperm tail
HP:0033525	Absent sperm axoneme central pair complex
HP:0000798	Oligozoospermia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007576_370	Chronotype	4.000000e-09
GCST007576_95	Chronotype	4.000000e-09
GCST012490_293	Femur bone mineral density x serum urate levels interaction	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004531	urate 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

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
bisphenol A	increases methylation	1
sodium arsenite	increases expression	1
calfactant	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
Sunitinib	decreases expression	1
Formaldehyde	decreases expression	1
Thimerosal	increases expression	1
Urethane	decreases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Aflatoxin M1	decreases expression	1
Okadaic Acid	increases expression	1
Nanotubes, Carbon	decreases expression, affects cotreatment	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)