CNBD2

Summary

CNBD2 (cyclic nucleotide binding domain containing 2, HGNC:16145) is a protein-coding gene on chromosome 20q11.23, encoding Cyclic nucleotide-binding domain-containing protein 2 (Q96M20). Essential for male fertility.

Predicted to enable cAMP binding activity. Predicted to be involved in spermatogenesis. Predicted to be located in cytosol.

Source: NCBI Gene 140894 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 121 total
• MANE Select transcript: NM_001365709

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16145
Approved symbol	CNBD2
Name	cyclic nucleotide binding domain containing 2
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	dJ954P9.1
Ensembl gene	ENSG00000149646
Ensembl biotype	protein_coding
Entrez	140894

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000349339, ENST00000373973, ENST00000463258, ENST00000489667, ENST00000538900, ENST00000614708, ENST00000622112

RefSeq mRNA: 4 — MANE Select: NM_001365709 NM_001207076, NM_001304367, NM_001365709, NM_080834

CCDS: CCDS13270, CCDS56189, CCDS77575, CCDS93033

Canonical transcript exons

ENST00000373973 — 12 exons

Exon	Start	End
ENSE00000991766	36008297	36008474
ENSE00000991767	36011137	36011257
ENSE00000991770	35972629	35972766
ENSE00000991771	35975949	35976002
ENSE00000991772	35980459	35980622
ENSE00000991773	35983982	35984138
ENSE00000991774	35984627	35984778
ENSE00000991775	35987395	35987533
ENSE00000991776	35995038	35995152
ENSE00001147260	36023602	36023771
ENSE00001856023	35968590	35968813
ENSE00003512577	36030357	36030700

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 93.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.4662 / max 85.6525, expressed in 1405 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184342	2.7938	1274
184341	0.6528	280
184343	0.0197	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	93.51	gold quality
right testis	UBERON:0004534	87.52	gold quality
left testis	UBERON:0004533	87.40	gold quality
testis	UBERON:0000473	85.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.71	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.52	silver quality
gastrocnemius	UBERON:0001388	83.44	gold quality
muscle of leg	UBERON:0001383	83.23	gold quality
quadriceps femoris	UBERON:0001377	83.03	silver quality
vastus lateralis	UBERON:0001379	82.70	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.51	gold quality
biceps brachii	UBERON:0001507	80.38	silver quality
deltoid	UBERON:0001476	79.36	silver quality
granulocyte	CL:0000094	77.88	gold quality
skeletal muscle tissue	UBERON:0001134	77.14	gold quality
kidney epithelium	UBERON:0004819	76.95	gold quality
islet of Langerhans	UBERON:0000006	76.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.97	silver quality
cerebellar hemisphere	UBERON:0002245	75.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	75.44	gold quality
cerebellar cortex	UBERON:0002129	75.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.97	gold quality
muscle tissue	UBERON:0002385	74.78	gold quality
monocyte	CL:0000576	74.42	gold quality
metanephros cortex	UBERON:0010533	74.25	gold quality
tendon of biceps brachii	UBERON:0008188	74.09	silver quality
right lobe of liver	UBERON:0001114	73.60	gold quality
cerebellum	UBERON:0002037	73.41	gold quality
leukocyte	CL:0000738	73.36	gold quality
mucosa of stomach	UBERON:0001199	73.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.62

Regulation

Is transcription factor: no

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cnbd2	ENSMUSG00000038085
rattus_norvegicus	Cnbd2	ENSRNOG00000019992
drosophila_melanogaster	CG12698	FBGN0030721
drosophila_melanogaster	CG8958	FBGN0030725
drosophila_melanogaster	CG14693	FBGN0037837

Protein

Protein identifiers

Cyclic nucleotide-binding domain-containing protein 2 — Q96M20 (reviewed: Q96M20)

All UniProt accessions (5): Q96M20, A0A087WUQ5, A0A087WVB8, Q4G141, U3KQM1

UniProt curated annotations — full annotation on UniProt →

Function. Essential for male fertility. Plays an important role in spermatogenesis and regulates sperm motility by controlling the development of the flagellar bending of sperm.

Subcellular location. Cytoplasm. Cytosol.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96M20-1	1	yes
Q96M20-2	2
Q96M20-3	3

RefSeq proteins (4): NP_001194005, NP_001291296, NP_001352638, NP_543024 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018488	cNMP-bd_CS	Conserved_site
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily

Pfam: PF00027

UniProt features (7 total): sequence variant 3, splice variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96M20-F1	69.79	0.20

Functional residue map

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

Ligand- & substrate-binding residues (1): 116–239

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, chr20q11, MODULE_48, MODULE_95, GOCC_MOTILE_CILIUM, GOCC_SPERM_MIDPIECE, GOCC_CILIUM, GOMF_CAMP_BINDING, STAT5A_02, GOMF_CYCLIC_NUCLEOTIDE_BINDING

GO Biological Process (1): spermatogenesis (GO:0007283)

GO Molecular Function (2): cAMP binding (GO:0030552), nucleotide binding (GO:0000166)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

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
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNBD2	KIAA1191	Q96A73	585
CNBD2	IQCF1	Q8N6M8	531
CNBD2	CNBD1	Q8NA66	521
CNBD2	EPB41L1	Q9H4G0	491
CNBD2	TOPAZ1	Q8N9V7	449
CNBD2	C14orf39	Q8N1H7	432
CNBD2	KLHDC3	Q9BQ90	429
CNBD2	SPEM1	Q8N4L4	417
CNBD2	DNAAF6	Q9NQM4	411
CNBD2	KLHL10	Q6JEL2	407
CNBD2	SLC71A1	Q96MC6	406
CNBD2	TERB1	Q8NA31	387
CNBD2	SPATA22	Q8NHS9	381
CNBD2	IFTAP	Q86VG3	377
CNBD2	SYCE3	A1L190	375

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A2ARP1, A2BID5, A7Z050, B6ZK77, O00750, O14976, O70344, O75460, P0C644, P16386, P19687, P35523, P35524, P54310, P70606, P97874, Q08CH3, Q0IH22, Q0P5V9, Q1LXZ7, Q3TRM4, Q5RDF1, Q640M6, Q64347, Q68J42, Q6IRN0, Q6JWV8, Q6P4K6, Q6P6V6, Q6PFW1, Q6R5J1, Q6ZN44, Q86VS3, Q8IZJ1, Q91WF3, Q95JR6, Q96M20, Q99KY4, Q9D2K4, Q9D5U8

Diamond homologs: Q95JR6, Q96M20, Q9D5U8, Q2K5E1, Q5SID7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2099 predictions. Top by Δscore:

Variant	Effect	Δscore
20:35972739:G:GT	donor_gain	1.0000
20:35972739:G:T	donor_gain	1.0000
20:35972762:GGGAT:G	donor_gain	1.0000
20:35972763:GGAT:G	donor_gain	1.0000
20:35972763:GGATG:G	donor_gain	1.0000
20:35972764:G:T	donor_gain	1.0000
20:35972764:GAT:G	donor_gain	1.0000
20:35972764:GATG:G	donor_gain	1.0000
20:35972767:G:GG	donor_gain	1.0000
20:35976000:G:GT	donor_gain	1.0000
20:35980627:G:GG	donor_gain	1.0000
20:35984618:A:AG	acceptor_gain	1.0000
20:35984619:C:G	acceptor_gain	1.0000
20:35984622:A:AG	acceptor_gain	1.0000
20:35984625:A:AG	acceptor_gain	1.0000
20:35984625:AG:A	acceptor_gain	1.0000
20:35984626:G:GT	acceptor_gain	1.0000
20:35984626:GG:G	acceptor_gain	1.0000
20:35984626:GGA:G	acceptor_gain	1.0000
20:35984626:GGAA:G	acceptor_gain	1.0000
20:35984626:GGAAA:G	acceptor_gain	1.0000
20:35984738:G:GT	donor_gain	1.0000
20:35984750:G:GT	donor_gain	1.0000
20:35984754:C:G	donor_gain	1.0000
20:35984758:G:GG	donor_gain	1.0000
20:35984775:TTAGG:T	donor_loss	1.0000
20:35984778:GG:G	donor_loss	1.0000
20:35984779:GT:G	donor_loss	1.0000
20:35987503:A:T	donor_gain	1.0000
20:36008475:G:GG	donor_gain	1.0000

AlphaMissense

3846 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:35980512:A:C	R99S	0.992
20:35980512:A:T	R99S	0.992
20:36023662:A:C	S444R	0.988
20:36023664:C:A	S444R	0.988
20:36023664:C:G	S444R	0.988
20:35984674:T:G	C204W	0.987
20:35980511:G:C	R99T	0.982
20:35984050:G:T	G159V	0.978
20:35983996:G:C	R141P	0.976
20:35984672:T:C	C204R	0.976
20:35984056:T:A	V161D	0.974
20:35984058:G:C	A162P	0.973
20:35984049:G:C	G159R	0.972
20:35995054:T:C	L291P	0.970
20:35995057:G:C	R292P	0.970
20:35984673:G:A	C204Y	0.968
20:35984700:T:A	V213D	0.966
20:35984091:T:C	F173L	0.965
20:35984093:C:A	F173L	0.965
20:35984093:C:G	F173L	0.965
20:35984694:T:C	L211P	0.962
20:36030419:T:C	L501P	0.961
20:35980601:C:A	A129D	0.958
20:35975973:T:C	F72L	0.957
20:35975975:T:A	F72L	0.957
20:35975975:T:G	F72L	0.957
20:35980613:G:C	R133P	0.956
20:35984050:G:A	G159D	0.956
20:35984670:T:A	V203D	0.954
20:36030410:G:C	R498P	0.954

dbSNP variants (sampled 300 via entrez): RS1000006990 (20:36022144 G>A), RS1000040268 (20:35980312 G>A), RS1000060955 (20:36021806 G>T), RS1000090579 (20:35980597 C>T), RS1000124315 (20:35968760 A>G), RS1000163432 (20:35991668 G>C), RS1000274054 (20:35988030 C>T), RS1000306965 (20:36003690 G>A), RS1000318870 (20:35973719 G>A,T), RS1000397450 (20:35976206 T>C), RS1000417733 (20:35954855 C>A,T), RS1000438496 (20:35995699 T>G), RS1000512727 (20:36009548 C>G), RS1000532386 (20:35955180 C>G,T), RS1000533295 (20:36002835 T>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010002_66	Refractive error	2.000000e-20
GCST012227_1149	Hip circumference adjusted for BMI	3.000000e-17
GCST90000025_646	Appendicular lean mass	8.000000e-22

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Niclosamide	increases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
S-Nitrosoglutathione	decreases expression	1

Clinical trials (associated diseases)

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