EFCAB9

Summary

EFCAB9 (EF-hand calcium binding domain 9, HGNC:34530) is a protein-coding gene on chromosome 5q35.1, encoding EF-hand calcium-binding domain-containing protein 9 (A8MZ26). Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. pH-dependent Ca(2+) sensor required to activate the CatSper channel.

This gene encodes a protein with a C-terminal EF-hand calcium-binding domain similar to that found in penta-EF-hand (PEF) protein family members. The EF-hand is a helix-loop-helix structure with a canonical twelve-residue sequence that coordinates a calcium molecule with pentagonal bipyramidal symmetry.

Source: NCBI Gene 285588 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 31 total
• MANE Select transcript: NM_001171183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34530
Approved symbol	EFCAB9
Name	EF-hand calcium binding domain 9
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000214360
Ensembl biotype	protein_coding
OMIM	618520
Entrez	285588

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000398186

RefSeq mRNA: 1 — MANE Select: NM_001171183 NM_001171183

CCDS: CCDS54946

Canonical transcript exons

ENST00000398186 — 4 exons

Exon	Start	End
ENSE00001531999	172203214	172203454
ENSE00001532000	172200566	172200742
ENSE00001532006	172199383	172199531
ENSE00001532008	172194172	172194308

Expression profiles

Bgee: expression breadth broad, 41 present calls, max score 83.66.

Top tissues by expression

91 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	83.66	gold quality
right testis	UBERON:0004534	78.07	gold quality
testis	UBERON:0000473	75.31	gold quality
left testis	UBERON:0004533	75.16	gold quality
cerebellum	UBERON:0002037	51.75	gold quality
cerebellar cortex	UBERON:0002129	51.69	gold quality
cerebellar hemisphere	UBERON:0002245	51.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	49.68	silver quality
right hemisphere of cerebellum	UBERON:0014890	49.43	gold quality
apex of heart	UBERON:0002098	39.65	silver quality
granulocyte	CL:0000094	39.55	gold quality
mucosa of transverse colon	UBERON:0004991	38.34	silver quality
skeletal muscle tissue	UBERON:0001134	37.22	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
muscle tissue	UBERON:0002385	35.38	silver quality
nucleus accumbens	UBERON:0001882	35.11	gold quality
putamen	UBERON:0001874	34.32	gold quality
vermiform appendix	UBERON:0001154	34.25	gold quality
adrenal tissue	UBERON:0018303	33.94	silver quality
gall bladder	UBERON:0002110	33.78	gold quality
bone marrow	UBERON:0002371	33.16	gold quality
islet of Langerhans	UBERON:0000006	32.98	gold quality
right adrenal gland	UBERON:0001233	32.23	silver quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
caudate nucleus	UBERON:0001873	31.51	silver quality
prefrontal cortex	UBERON:0000451	31.10	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting EFCAB9, 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-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
mus_musculus	Efcab9	ENSMUSG00000044056
rattus_norvegicus	Efcab9	ENSRNOG00000004142
drosophila_melanogaster	TpnC4	FBGN0033027
caenorhabditis_elegans		WBGENE00000285
caenorhabditis_elegans		WBGENE00000287
caenorhabditis_elegans	pat-10	WBGENE00003934
caenorhabditis_elegans		WBGENE00006583
caenorhabditis_elegans		WBGENE00008453
caenorhabditis_elegans	F35C12.3	WBGENE00009408
caenorhabditis_elegans		WBGENE00015264

Paralogs (20): CABP7 (ENSG00000100314), CABP5 (ENSG00000105507), CALML4 (ENSG00000129007), CALM2 (ENSG00000143933), CETN2 (ENSG00000147400), CETN3 (ENSG00000153140), CABP1 (ENSG00000157782), CALM3 (ENSG00000160014), CABP2 (ENSG00000167791), CALML6 (ENSG00000169885), EFCAB3 (ENSG00000172421), EFCAB12 (ENSG00000172771), CABP4 (ENSG00000175544), CETN1 (ENSG00000177143), CALML3 (ENSG00000178363), CALML5 (ENSG00000178372), CALN1 (ENSG00000183166), CALM1 (ENSG00000198668), EFCAB2 (ENSG00000203666), EFCAB7 (ENSG00000203965)

Protein

Protein identifiers

EF-hand calcium-binding domain-containing protein 9 — A8MZ26 (reviewed: A8MZ26)

All UniProt accessions (1): A8MZ26

UniProt curated annotations — full annotation on UniProt →

Function. Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. pH-dependent Ca(2+) sensor required to activate the CatSper channel. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Associates with the CatSper complex via direct interaction with CATSPERZ, and senses intracellular Ca(2+). Together with CATSPERZ, associates with the CatSper channel pore and is required for the two-row structure of each single CatSper channel.

Subunit / interactions. Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, CATSPERT, CATSPERQ, CATSPERH and EFCAB9. HSPA1 may be an additional auxiliary complex member. The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel. The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively. CATSPERH interacts with CATSPERB, further stabilizing the complex. CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane. Interacts with CATSPERZ; the interaction is direct, Ca(2+)-dependent and connects EFCAB9 with the CatSper complex. Dissociates from CATSPERZ at elevated pH.

Subcellular location. Cytoplasm. Cell projection. Cilium. Flagellum.

RefSeq proteins (1): NP_001164654* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR042798	EFCAB9	Family

Pfam: PF13499

UniProt features (12 total): binding site 6, domain 3, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MZ26-F1	94.00	0.86

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 (6): 155; 160; 58; 69; 149; 153

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 49 (showing top): GOBP_MALE_GAMETE_GENERATION, GOBP_SPERM_CAPACITATION, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_CELL_MATURATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOCC_VOLTAGE_GATED_CALCIUM_CHANNEL_COMPLEX, GOCC_MOTILE_CILIUM, GOCC_CATION_CHANNEL_COMPLEX, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOCC_SPERM_PRINCIPAL_PIECE, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (3): spermatogenesis (GO:0007283), flagellated sperm motility (GO:0030317), sperm capacitation (GO:0048240)

GO Molecular Function (3): calcium ion binding (GO:0005509), calcium ion sensor activity (GO:0061891), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), CatSper complex (GO:0036128), sperm principal piece (GO:0097228), 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	3
developmental process involved in reproduction	2
male gamete generation	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
spermatid development	1
cellular process involved in reproduction in multicellular organism	1
cell maturation	1
metal ion binding	1
calcium ion binding	1
metal ion sensor activity	1
cation binding	1
intracellular anatomical structure	1
voltage-gated calcium channel complex	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

1253 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFCAB9	CATSPERZ	Q9NTU4	951
EFCAB9	CATSPER1	Q8NEC5	922
EFCAB9	CATSPER4	Q7RTX7	806
EFCAB9	CATSPERB	Q9H7T0	765
EFCAB9	CATSPER3	Q86XQ3	740
EFCAB9	CATSPER2	Q96P56	705
EFCAB9	CATSPERE	Q5SY80	626
EFCAB9	CATSPERT	Q53TS8	626
EFCAB9	CATSPERD	Q86XM0	609
EFCAB9	SLC66A1LP	A1A4F0	519
EFCAB9	KCNU1	A8MYU2	460
EFCAB9	LRRC52	Q8N7C0	455
EFCAB9	HVCN1	Q96D96	399
EFCAB9	UBTD2	Q8WUN7	398
EFCAB9	ABHD2	P08910	377

IntAct

0 interactions, top by confidence:

BioGRID (1): EFCAB9 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2RT91, A3LNC4, A6H7C9, A8MZ26, O01326, O02217, O36972, P07164, P0C964, P0C965, P0C966, P0C9F5, P0C9S7, P0C9U2, P0C9U7, P25027, P39047, P41048, P45964, P86196, Q03569, Q04231, Q05930, Q11083, Q21534, Q3HRN8, Q3HRP1, Q3HRP5, Q5M6W3, Q65128, Q6CU48, Q6NUM6, Q75LU8, Q76U48, Q7FRS8, Q7FZF1, Q7Z5J8, Q89925, Q8BH53, Q8LAS7

Diamond homologs: A8MZ26, Q9DAM2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EFCAB9	“form complex”	“CatSpermasome complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

592 predictions. Top by Δscore:

Variant	Effect	Δscore
5:172199382:GAT:G	acceptor_gain	1.0000
5:172200743:G:GA	donor_loss	1.0000
5:172200743:G:GG	donor_gain	1.0000
5:172200744:T:G	donor_loss	1.0000
5:172194292:C:T	donor_gain	0.9900
5:172194307:TGG:T	donor_loss	0.9900
5:172194309:G:GG	donor_gain	0.9900
5:172194310:T:A	donor_loss	0.9900
5:172196305:C:G	donor_gain	0.9900
5:172199377:TAACA:T	acceptor_loss	0.9900
5:172199378:A:AG	acceptor_gain	0.9900
5:172199378:AACAG:A	acceptor_loss	0.9900
5:172199379:ACAG:A	acceptor_loss	0.9900
5:172199380:CA:C	acceptor_loss	0.9900
5:172199381:A:AG	acceptor_gain	0.9900
5:172199382:G:GA	acceptor_loss	0.9900
5:172199382:G:GG	acceptor_gain	0.9900
5:172199382:GATGT:G	acceptor_gain	0.9900
5:172199411:T:G	acceptor_gain	0.9900
5:172200561:A:AG	acceptor_gain	0.9900
5:172200565:GAACC:G	acceptor_gain	0.9900
5:172200739:CAAT:C	donor_gain	0.9900
5:172200741:AT:A	donor_gain	0.9900
5:172200745:AA:A	donor_loss	0.9900
5:172203206:A:AG	acceptor_gain	0.9900
5:172194304:GAATG:G	donor_gain	0.9800
5:172194312:A:AG	donor_gain	0.9800
5:172194313:G:GG	donor_gain	0.9800
5:172199407:ATCAT:A	acceptor_gain	0.9800
5:172200564:A:AG	acceptor_gain	0.9800

AlphaMissense

1325 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:172200611:T:C	F111L	0.988
5:172200613:T:A	F111L	0.988
5:172200613:T:G	F111L	0.988
5:172199448:T:C	F68L	0.982
5:172199450:T:A	F68L	0.982
5:172199450:T:G	F68L	0.982
5:172203232:T:C	F161L	0.981
5:172203234:T:A	F161L	0.981
5:172203234:T:G	F161L	0.981
5:172200584:T:C	F102L	0.979
5:172200586:T:A	F102L	0.979
5:172200586:T:G	F102L	0.979
5:172199496:T:C	F84L	0.978
5:172199498:C:A	F84L	0.978
5:172199498:C:G	F84L	0.978
5:172194269:T:C	F33L	0.975
5:172194271:T:A	F33L	0.975
5:172194271:T:G	F33L	0.975
5:172203233:T:C	F161S	0.973
5:172200585:T:C	F102S	0.971
5:172200674:T:C	F132L	0.968
5:172200676:T:A	F132L	0.968
5:172200676:T:G	F132L	0.968
5:172194303:T:C	L44S	0.964
5:172194234:T:C	L21S	0.963
5:172199404:T:C	L53P	0.963
5:172199401:T:C	F52S	0.959
5:172194247:C:A	N25K	0.955
5:172194247:C:G	N25K	0.955
5:172200609:T:A	V110D	0.952

dbSNP variants (sampled 300 via entrez): RS1000604132 (5:172200495 C>A), RS1000784738 (5:172201058 C>A), RS1000876768 (5:172195222 T>A), RS1001133900 (5:172195179 AATAAAAAT>A), RS1001220239 (5:172198353 TAAA>T), RS1001272692 (5:172198173 T>G), RS1001635472 (5:172199937 T>A), RS1001668056 (5:172200153 A>C), RS1001822232 (5:172194653 C>A), RS1002003611 (5:172201356 A>G), RS1002187116 (5:172196263 C>T), RS1002560970 (5:172195941 C>T), RS1002843259 (5:172197408 G>C), RS1002865762 (5:172193381 G>A), RS1002931012 (5:172197565 A>G)

Disease associations

OMIM: gene MIM:618520 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
Arsenic	affects methylation	1
Malathion	increases expression	1

Clinical trials (associated diseases)

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