EFHB

Summary

EFHB (EF-hand domain family member B, HGNC:26330) is a protein-coding gene on chromosome 3p24.3, encoding EF-hand domain-containing family member B (Q8N7U6). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

Enables calcium ion sensor activity. Involved in regulation of calcineurin-NFAT signaling cascade and regulation of store-operated calcium entry. Located in axonemal microtubule.

Source: NCBI Gene 151651 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 137 total — 2 pathogenic
• MANE Select transcript: NM_144715

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26330
Approved symbol	EFHB
Name	EF-hand domain family member B
Location	3p24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25200, CFAP21
Ensembl gene	ENSG00000163576
Ensembl biotype	protein_coding
Entrez	151651

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000295824, ENST00000344838, ENST00000389256, ENST00000440022, ENST00000467602, ENST00000474780, ENST00000498089

RefSeq mRNA: 2 — MANE Select: NM_144715 NM_001330688, NM_144715

CCDS: CCDS33715, CCDS82744

Canonical transcript exons

ENST00000295824 — 13 exons

Exon	Start	End
ENSE00001076161	19884403	19884615
ENSE00001076163	19882550	19882731
ENSE00001505285	19888444	19888651
ENSE00001558804	19879472	19879804
ENSE00001900720	19933230	19934217
ENSE00003468226	19920505	19920567
ENSE00003482325	19915303	19915413
ENSE00003486692	19918232	19918412
ENSE00003544891	19905620	19905749
ENSE00003546035	19919833	19919976
ENSE00003619329	19896687	19896841
ENSE00003651084	19898778	19898845
ENSE00003679591	19899432	19899515

Expression profiles

Bgee: expression breadth ubiquitous, 171 present calls, max score 97.49.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0239 / max 41.6695, expressed in 494 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41412	0.7594	406
41411	0.2645	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	97.49	gold quality
bronchus	UBERON:0002185	95.72	gold quality
right uterine tube	UBERON:0001302	90.30	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.07	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.76	gold quality
oviduct epithelium	UBERON:0004804	86.56	gold quality
sperm	CL:0000019	85.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.52	gold quality
left testis	UBERON:0004533	83.53	gold quality
right testis	UBERON:0004534	82.79	gold quality
testis	UBERON:0000473	81.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.20	gold quality
fallopian tube	UBERON:0003889	80.68	gold quality
epithelium of nasopharynx	UBERON:0001951	76.21	gold quality
nasal cavity epithelium	UBERON:0005384	74.93	silver quality
stromal cell of endometrium	CL:0002255	73.32	gold quality
caput epididymis	UBERON:0004358	73.11	gold quality
sural nerve	UBERON:0015488	72.28	gold quality
metanephros cortex	UBERON:0010533	71.95	gold quality
nasal cavity mucosa	UBERON:0001826	71.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	70.63	gold quality
cortical plate	UBERON:0005343	69.77	gold quality
right lung	UBERON:0002167	69.40	gold quality
hypothalamus	UBERON:0001898	68.83	gold quality
spinal cord	UBERON:0002240	68.04	gold quality
right adrenal gland cortex	UBERON:0035827	67.99	gold quality
amygdala	UBERON:0001876	67.92	gold quality
right adrenal gland	UBERON:0001233	67.14	gold quality
ventricular zone	UBERON:0003053	66.96	gold quality
tibial nerve	UBERON:0001323	66.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting EFHB, 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-4668-3P	100.00	68.74	2635
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-618	97.62	67.46	861
HSA-MIR-4680-5P	96.43	67.15	893

Literature-anchored findings (GeneRIF, showing 2)

• EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF Interaction (PMID:30481768)
• EFHB is a new store-operated Ca2+ entry regulator that modulates STIM1-SARAF interaction. (PMID:30481768)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	efhb	ENSDARG00000069703
mus_musculus	Efhb	ENSMUSG00000023931
rattus_norvegicus	Efhb	ENSRNOG00000012618
caenorhabditis_elegans		WBGENE00013028

Paralogs (2): EFHC1 (ENSG00000096093), EFHC2 (ENSG00000183690)

Protein

Protein identifiers

EF-hand domain-containing family member B — Q8N7U6 (reviewed: Q8N7U6)

Alternative names: Cilia- and flagella-associated protein 21

All UniProt accessions (3): Q8N7U6, H7C0U4, H9KV82

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Cytosolic sensor for calcium, modulates the interaction of STIM1 and ORAI1 upon store depletion and the activation of store-operated Ca(2+) entry (SOCE) and NFAT translocation from cytosol to nucleus.

Subunit / interactions. Microtubule inner protein component of sperm flagellar doublet microtubules. Interacts with STIM1 and ORAI1; the interactions take place upon Ca(2+)-store depletion and dissociate through a Ca(2+)-dependent mechanism. Interaction with STIM1 inhibits STIM1 interaction with SARAF.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium axoneme. Flagellum axoneme.

Tissue specificity. Expressed in airway epithelial cells.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N7U6-1	1	yes
Q8N7U6-2	2
Q8N7U6-3	3

RefSeq proteins (2): NP_001317617, NP_653316* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR040193	EFHC1/EFHC2/EFHB	Family
IPR057428	EFHB_EF-hand_C	Domain

Pfam: PF13499, PF25325

UniProt features (27 total): binding site 8, sequence variant 6, sequence conflict 6, splice variant 4, domain 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7UNG	ELECTRON MICROSCOPY	3.6
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N7U6-F1	63.23	0.05

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 (8): 621; 574; 578; 580; 585; 610; 612; 614

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 104 (showing top): GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, RYTTCCTG_ETS2_B, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, NERF_Q2, GOCC_CYTOPLASMIC_REGION, GOCC_MOTILE_CILIUM, GOCC_CYTOPLASMIC_MICROTUBULE

GO Biological Process (6): calcium ion transport (GO:0006816), flagellated sperm motility (GO:0030317), negative regulation of protein binding (GO:0032091), regulation of calcineurin-NFAT signaling cascade (GO:0070884), regulation of store-operated calcium entry (GO:2001256), monoatomic ion transport (GO:0006811)

GO Molecular Function (4): calcium ion binding (GO:0005509), calcium ion sensor activity (GO:0061891), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): axonemal microtubule (GO:0005879), sperm flagellum (GO:0036126), axonemal A tubule inner sheath (GO:0160111), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), 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
metal ion transport	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
protein binding	1
regulation of protein binding	1
negative regulation of binding	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-mediated signaling	1
store-operated calcium entry	1
regulation of calcium ion transport	1
transport	1
metal ion binding	1
calcium ion binding	1
metal ion sensor activity	1
binding	1
cation binding	1
cytoplasmic microtubule	1
axoneme	1
9+2 motile cilium	1
A axonemal microtubule	1
axonemal microtubule doublet inner sheath	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

2066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFHB	SARAF	Q96BY9	718
EFHB	CRACR2A	Q9BSW2	619
EFHB	STYXL2	Q5VZP5	516
EFHB	CAPSL	Q8WWF8	507
EFHB	SCLY	Q96I15	476
EFHB	C9orf43	Q8TAL5	446
EFHB	RAVER1	Q8IY67	442
EFHB	LRFN4	Q6PJG9	441
EFHB	ESPNL	Q6ZVH7	435
EFHB	IRAG1	Q9Y6F6	434
EFHB	ORAI1	Q96D31	423
EFHB	STIM1	Q13586	422
EFHB	RCE1	Q9Y256	419
EFHB	GLRB	P48167	417
EFHB	GUCY1A2	P33402	411

IntAct

7 interactions, top by confidence:

A	B	Type	Score
STIM1	EFHB	psi-mi:“MI:0915”(physical association)	0.500
STIM1	EFHB	psi-mi:“MI:0914”(association)	0.500
ORAI1	EFHB	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (3): EFHB (Affinity Capture-MS), EFHB (Affinity Capture-MS), EFHB (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1B0GTD5, A0A1B0GUX0, A0A3Q1MT14, A4D263, A6NL82, A6QQL5, A8QW39, B0UXH9, B5X5D0, B9EJX3, E1B9R1, F1MMV1, Q148A4, Q1JPL0, Q2T9T0, Q32KQ1, Q32L72, Q32L77, Q32P67, Q3V0J4, Q5BN46, Q5NC57, Q5NC83, Q5SPV6, Q5SS90, Q5SVJ3, Q5VTT2, Q5VZQ5, Q66HC0, Q66HR9, Q6AYM0, Q6NXP0, Q6P3G4, Q6ZVS7, Q80X60, Q8CDT5, Q8CDU5, Q8N5S3, Q8N7U6, Q8N865

Diamond homologs: A5PJZ1, F1MMV1, O18757, P02597, P28583, P48593, Q0DYK7, Q2QVG8, Q40302, Q6AVI8, Q6NUK1, Q8BMD8, Q8CDU5, Q8N7U6, Q9FXQ3, Q9M9V8, Q9SSF8, Q9SZM3, A0A5K1K8H0, A8CEP3, O49717, O60041, P02612, P04464, P05419, P05933, P06704, P06787, P0DP23, P0DP24, P0DP26, P0DP27, P0DP29, P0DP33, P11121, P13832, P14533, P18061, P24032, P24844

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	118
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
57979	GRCh38/hg38 3p24.3-24.2(chr3:19915382-25537973)x3	Pathogenic
687662	GRCh37/hg19 3p24.3-24.1(chr3:19064852-26448689)x1	Pathogenic

SpliceAI

2373 predictions. Top by Δscore:

Variant	Effect	Δscore
3:19884401:A:AC	donor_gain	1.0000
3:19884402:C:CC	donor_gain	1.0000
3:19884423:A:AC	donor_gain	1.0000
3:19884424:C:CC	donor_gain	1.0000
3:19884515:T:TA	donor_gain	1.0000
3:19896681:A:AC	donor_gain	1.0000
3:19896682:C:CC	donor_gain	1.0000
3:19896739:A:C	donor_gain	1.0000
3:19896743:T:A	donor_gain	1.0000
3:19896837:AACTC:A	acceptor_gain	1.0000
3:19896839:CTC:C	acceptor_gain	1.0000
3:19896840:TC:T	acceptor_gain	1.0000
3:19896841:CC:C	acceptor_gain	1.0000
3:19896841:CCTA:C	acceptor_loss	1.0000
3:19896842:C:CC	acceptor_gain	1.0000
3:19896845:T:TC	acceptor_gain	1.0000
3:19898029:C:CA	donor_gain	1.0000
3:19898841:CAATG:C	acceptor_gain	1.0000
3:19898844:TG:T	acceptor_gain	1.0000
3:19898846:C:CC	acceptor_gain	1.0000
3:19899430:A:AC	donor_gain	1.0000
3:19899431:C:CC	donor_gain	1.0000
3:19899431:CGGAT:C	donor_gain	1.0000
3:19905613:AACTT:A	donor_loss	1.0000
3:19905614:ACTT:A	donor_loss	1.0000
3:19905615:CTTAC:C	donor_loss	1.0000
3:19905616:TTACA:T	donor_loss	1.0000
3:19905617:T:TC	donor_loss	1.0000
3:19905618:A:AC	donor_gain	1.0000
3:19905618:A:T	donor_loss	1.0000

AlphaMissense

5474 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:19888511:G:C	F622L	0.994
3:19888511:G:T	F622L	0.994
3:19888513:A:G	F622L	0.994
3:19896723:A:C	F563L	0.990
3:19896723:A:T	F563L	0.990
3:19896725:A:G	F563L	0.990
3:19888512:A:G	F622S	0.987
3:19888620:A:G	L586P	0.985
3:19888502:A:C	F625L	0.983
3:19888502:A:T	F625L	0.983
3:19888504:A:G	F625L	0.983
3:19896702:G:C	F570L	0.983
3:19896702:G:T	F570L	0.983
3:19896704:A:G	F570L	0.983
3:19888635:A:T	I581K	0.981
3:19888552:A:G	C609R	0.980
3:19896748:A:G	L555P	0.978
3:19888510:C:G	A623P	0.977
3:19896757:C:G	R552P	0.976
3:19905692:C:T	G449E	0.975
3:19888500:A:G	L626P	0.974
3:19888527:A:T	I617N	0.974
3:19896744:C:A	K556N	0.974
3:19896744:C:G	K556N	0.974
3:19896703:A:G	F570S	0.973
3:19888550:A:C	C609W	0.971
3:19888563:A:G	L605P	0.971
3:19888527:A:C	I617S	0.970
3:19888551:C:T	C609Y	0.969
3:19919905:A:C	F308L	0.969

dbSNP variants (sampled 300 via entrez): RS1000046787 (3:19896370 C>T), RS1000126061 (3:19883513 A>G), RS1000162183 (3:19931491 G>A,C), RS1000179100 (3:19925190 C>T), RS1000236300 (3:19931257 A>T), RS1000330954 (3:19919224 T>C), RS1000332591 (3:19882994 TTTTTTC>T,TTTTTTCTTTTTC), RS1000357944 (3:19947822 G>C,T), RS1000397094 (3:19913903 G>A), RS1000408981 (3:19883773 G>C), RS1000538648 (3:19909028 A>C), RS1000702770 (3:19906283 C>G,T), RS1000794672 (3:19913527 G>A), RS1000842758 (3:19925426 C>A,G), RS1000849822 (3:19941417 G>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

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	decreases expression	1
cupric oxide	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Nickel	decreases expression	1
Oxygen	increases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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