CBY3

Summary

CBY3 (chibby family member 3, HGNC:33278) is a protein-coding gene on chromosome 5q35.3, encoding Sperm annulus positioning complex subunit Chibby3 (A6NI87). Plays a key role in the correct positioning of the annulus, a septin-based ring structure in the sperm flagellum, serving both as a physical barrier and a membrane diffusion barrier that separates the midpiece (MP) from the principal piece (PP).

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 6 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001164444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33278
Approved symbol	CBY3
Name	chibby family member 3
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204659
Ensembl biotype	protein_coding
OMIM	620892
Entrez	646019

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000376974

RefSeq mRNA: 1 — MANE Select: NM_001164444 NM_001164444

CCDS: CCDS47354

Canonical transcript exons

ENST00000376974 — 2 exons

Exon	Start	End
ENSE00001472312	179678560	179679265
ENSE00001690939	179680873	179681034

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 91.04.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0062 / max 6.7663, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65228	0.0062	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.04	gold quality
right testis	UBERON:0004534	78.20	gold quality
left testis	UBERON:0004533	77.71	gold quality
testis	UBERON:0000473	76.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.17	gold quality
substantia nigra	UBERON:0002038	64.24	gold quality
right uterine tube	UBERON:0001302	63.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.94	gold quality
hypothalamus	UBERON:0001898	61.45	gold quality
nucleus accumbens	UBERON:0001882	60.56	gold quality
Ammon’s horn	UBERON:0001954	60.47	gold quality
temporal lobe	UBERON:0001871	60.02	gold quality
amygdala	UBERON:0001876	60.00	gold quality
putamen	UBERON:0001874	59.85	gold quality
apex of heart	UBERON:0002098	59.46	gold quality
right coronary artery	UBERON:0001625	59.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.43	gold quality
cerebellum	UBERON:0002037	58.24	gold quality
cerebellar cortex	UBERON:0002129	58.11	gold quality
cerebellar hemisphere	UBERON:0002245	58.01	gold quality
right ovary	UBERON:0002118	57.15	gold quality
pituitary gland	UBERON:0000007	56.61	gold quality
caudate nucleus	UBERON:0001873	56.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	56.19	gold quality
brain	UBERON:0000955	55.80	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	55.37	gold quality
anterior cingulate cortex	UBERON:0009835	55.27	gold quality
stromal cell of endometrium	CL:0002255	55.12	silver quality
left ovary	UBERON:0002119	55.10	gold quality
metanephros cortex	UBERON:0010533	55.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.23

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cby3	ENSMUSG00000050087
rattus_norvegicus	Cby3	ENSRNOG00000066223

Paralogs (3): CBY1 (ENSG00000100211), CCDC70 (ENSG00000123171), CBY2 (ENSG00000174015)

Protein

Protein identifiers

Sperm annulus positioning complex subunit Chibby3 — A6NI87 (reviewed: A6NI87)

All UniProt accessions (1): A6NI87

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role in the correct positioning of the annulus, a septin-based ring structure in the sperm flagellum, serving both as a physical barrier and a membrane diffusion barrier that separates the midpiece (MP) from the principal piece (PP). This positioning is essential for proper sperm motility and function. CBY3 interacts with CIBAR1 to form a complex which localizes to the curved membrane region of the flagellar pocket. By doing so, may provide stability and rigidity to the periannular membrane to prevent membrane deformation. This function is crucial for halting annulus migration at the proximal end of the fibrous sheath-containing PP.

Subunit / interactions. Homodimer. Interacts with CIBAR1 (via BAR-like domain); both proteins form a ninefold symmetric structure at the flagellar base; are recruited to the annulus in a mutually dependent manner and regulate annulus positioning.

Subcellular location. Cell projection. Cilium. Flagellum.

Miscellaneous. ‘Chibby’ is Japanese for ‘small’; the gene was so named for the RNAi phenotype seen in flies.

Similarity. Belongs to the chibby family.

RefSeq proteins (1): NP_001157916* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028118	Chibby_fam	Family

Pfam: PF14645

UniProt features (6 total): region of interest 2, mutagenesis site 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NI87-F1	68.59	0.18

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
102	reduced interaction with cibar1.
117	reduced interaction with cibar1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 28 (showing top): GOBP_MALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOCC_MOTILE_CILIUM, GOCC_CILIUM, GOCC_SPERM_ANNULUS, GOCC_9PLUS2_MOTILE_CILIUM, GSE14386_UNTREATED_VS_IFNA_TREATED_ACT_PBMC_MS_PATIENT_UP, GSE13306_TREG_VS_TCONV_SPLEEN_DN, GSE15659_CD45RA_NEG_CD4_TCELL_VS_RESTING_TREG_UP, GSE15659_CD45RA_NEG_CD4_TCELL_VS_NONSUPPRESSIVE_TCELL_UP, GSE15659_CD45RA_NEG_CD4_TCELL_VS_ACTIVATED_TREG_UP, GSE15659_RESTING_TREG_VS_NONSUPPRESSIVE_TCELL_UP, GSE15659_NONSUPPRESSIVE_TCELL_VS_ACTIVATED_TREG_UP, GSE19825_NAIVE_VS_DAY3_EFF_CD8_TCELL_UP, GSE20366_EX_VIVO_VS_DEC205_CONVERSION_NAIVE_CD4_TCELL_DN

GO Biological Process (2): spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (4): sperm annulus (GO:0097227), cilium (GO:0005929), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
sperm flagellum	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBY3	CBY2	Q8NA61	708
CBY3	SAXO1	Q8IYX7	495
CBY3	ADAD2	Q8NCV1	478
CBY3	ANKRD31	Q8N7Z5	473
CBY3	MEIOB	Q8N635	422
CBY3	ASB15	Q8WXK1	413
CBY3	MEIOC	A2RUB1	410
CBY3	SUDS3	Q9H7L9	391
CBY3	CHD3	Q12873	367
CBY3	DRC11	Q86XH1	360
CBY3	CHD1	O14646	357
CBY3	ADAM29	Q9UKF5	306
CBY3	PPP2R3A	Q06190	287
CBY3	TNP1	P09430	273
CBY3	STRA8	Q7Z7C7	264

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A0D9SF12, A2A8T7, A6H7E2, A6NF36, A6NFA0, A6NI87, E1C7U0, P03246, P03247, P0DO92, P14355, P14683, Q0VG49, Q1HVF6, Q32LN6, Q3KPU7, Q3KSS3, Q4V7D2, Q4ZG55, Q5DU28, Q5JX69, Q5JX71, Q5R7E2, Q5U4U4, Q642A3, Q6NRW0, Q6P1U0, Q6P4J6, Q6P9N1, Q6PEX7, Q6X4T0, Q7L3B6, Q7SYV9, Q7T346, Q80Y73, Q8BJS8, Q8CF25, Q8IWB6, Q8N6T0, Q8NCU1

Diamond homologs: A6NI87, A6QQS3, Q6AXV6, Q8K4I6, Q8MJK1, Q9CVN6, Q9D1C2, Q9Y3M2, Q32MG2, Q8NA61, Q95JK3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

236 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179680868:CATA:C	donor_loss	0.9900
5:179680870:TACC:T	donor_loss	0.9900
5:179680871:A:AC	donor_gain	0.9900
5:179680871:A:C	donor_loss	0.9900
5:179680871:ACCAT:A	donor_gain	0.9900
5:179680872:C:CC	donor_gain	0.9900
5:179680872:CCAT:C	donor_gain	0.9900
5:179680872:CCATC:C	donor_gain	0.9900
5:179679263:C:CC	acceptor_gain	0.9800
5:179680832:ATC:A	donor_gain	0.9800
5:179679261:CG:C	acceptor_gain	0.9700
5:179680867:ACAT:A	donor_loss	0.9700
5:179680871:AC:A	donor_gain	0.9600
5:179680872:CC:C	donor_gain	0.9600
5:179679262:GC:G	acceptor_loss	0.9500
5:179679264:T:G	acceptor_loss	0.9500
5:179679266:C:CC	acceptor_gain	0.9500
5:179679260:GCG:G	acceptor_gain	0.9400
5:179679261:CGC:C	acceptor_gain	0.9400
5:179679258:GGGCG:G	acceptor_gain	0.9300
5:179679265:G:C	acceptor_loss	0.9300
5:179679259:GGCG:G	acceptor_gain	0.9200
5:179680872:CCA:C	donor_gain	0.9200
5:179679262:GCTG:G	acceptor_loss	0.8900
5:179679263:CTGC:C	acceptor_loss	0.8900
5:179679264:TGC:T	acceptor_loss	0.8900
5:179679265:GCTG:G	acceptor_loss	0.8900
5:179679266:C:CA	acceptor_loss	0.8900
5:179679267:T:G	acceptor_loss	0.8900
5:179679275:A:T	acceptor_loss	0.8700

AlphaMissense

1549 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:179678910:G:C	F134L	0.983
5:179678910:G:T	F134L	0.983
5:179678912:A:G	F134L	0.983
5:179678895:C:A	W139C	0.965
5:179678895:C:G	W139C	0.965
5:179678897:A:G	W139R	0.961
5:179678897:A:T	W139R	0.961
5:179679048:G:C	F88L	0.961
5:179679048:G:T	F88L	0.961
5:179679050:A:G	F88L	0.961
5:179678911:A:G	F134S	0.951
5:179678911:A:C	F134C	0.921
5:179678912:A:C	F134V	0.917
5:179678916:G:C	F132L	0.917
5:179678916:G:T	F132L	0.917
5:179678918:A:G	F132L	0.917
5:179678912:A:T	F134I	0.915
5:179678896:C:G	W139S	0.895
5:179678758:A:G	L185P	0.892
5:179679000:G:C	F104L	0.891
5:179679000:G:T	F104L	0.891
5:179679002:A:G	F104L	0.891
5:179678776:A:G	L179P	0.890
5:179678772:C:A	K180N	0.884
5:179678772:C:G	K180N	0.884
5:179678770:A:G	L181P	0.878
5:179678745:C:A	M189I	0.858
5:179678745:C:G	M189I	0.858
5:179678745:C:T	M189I	0.858
5:179679075:A:C	F79L	0.856

dbSNP variants (sampled 300 via entrez): RS1000132233 (5:179680792 G>A), RS1000647566 (5:179679366 C>G,T), RS1000933856 (5:179681301 A>C), RS1001363741 (5:179682467 T>C), RS1002234180 (5:179682975 G>A), RS1002979978 (5:179681286 A>T), RS1003280526 (5:179678853 G>A), RS1004247603 (5:179680012 C>T), RS1004550669 (5:179679132 G>A,C,T), RS1004824560 (5:179680434 A>T), RS1004967563 (5:179678844 G>A,C), RS10053812 (5:179682944 C>T), RS1006614169 (5:179678146 A>G), RS10066644 (5:179682337 G>A), RS1006670040 (5:179682079 C>T)

Disease associations

OMIM: gene MIM:620892 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003518_46	Daytime sleep phenotypes	1.000000e-06
GCST003518_7	Daytime sleep phenotypes	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, affects methylation	2
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
Lipopolysaccharides	increases expression, affects cotreatment, affects response to substance	1
Valproic Acid	decreases methylation	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry