SPEF1

Summary

SPEF1 (sperm flagellar and cilia associated 1, HGNC:15874) is a protein-coding gene on chromosome 20p13, encoding Sperm flagellar protein 1 (Q9Y4P9). Microtubule-associated protein involved in the stabilization of microtubules along the axis of migration during radial intercalation.

Enables actin binding activity. Involved in filopodium assembly and lamellipodium assembly. Located in several cellular components, including basolateral plasma membrane; lamellipodium; and microvillus.

Source: NCBI Gene 25876 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_015417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15874
Approved symbol	SPEF1
Name	sperm flagellar and cilia associated 1
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434I114, SPEF1A, CLAMP
Ensembl gene	ENSG00000101222
Ensembl biotype	protein_coding
OMIM	610674
Entrez	25876

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000379756, ENST00000463490, ENST00000471499, ENST00000866622

RefSeq mRNA: 1 — MANE Select: NM_015417 NM_015417

CCDS: CCDS13063

Canonical transcript exons

ENST00000379756 — 7 exons

Exon	Start	End
ENSE00001482378	3778746	3778806
ENSE00001482385	3778951	3778990
ENSE00003466928	3777504	3778319
ENSE00003468420	3781179	3781448
ENSE00003491524	3778421	3778544
ENSE00003531960	3779196	3779352
ENSE00003665237	3779664	3779775

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 96.23.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1945 / max 12.4985, expressed in 96 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186170	0.1945	96

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.31	gold quality
caudate nucleus	UBERON:0001873	88.20	gold quality
putamen	UBERON:0001874	87.75	gold quality
nucleus accumbens	UBERON:0001882	87.59	gold quality
epithelium of bronchus	UBERON:0002031	85.30	gold quality
bronchial epithelial cell	CL:0002328	85.21	gold quality
bronchus	UBERON:0002185	84.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.53	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	80.47	gold quality
prefrontal cortex	UBERON:0000451	79.80	gold quality
left testis	UBERON:0004533	79.74	gold quality
nasal cavity epithelium	UBERON:0005384	79.29	gold quality
right testis	UBERON:0004534	78.88	gold quality
right frontal lobe	UBERON:0002810	77.21	gold quality
telencephalon	UBERON:0001893	77.06	gold quality
testis	UBERON:0000473	76.39	gold quality
frontal cortex	UBERON:0001870	76.24	gold quality
Ammon’s horn	UBERON:0001954	75.84	gold quality
forebrain	UBERON:0001890	75.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	75.59	gold quality
cingulate cortex	UBERON:0003027	75.40	gold quality
neocortex	UBERON:0001950	75.33	gold quality
inferior olivary complex	UBERON:0002127	75.23	silver quality
anterior cingulate cortex	UBERON:0009835	75.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.85	gold quality
cerebral cortex	UBERON:0000956	74.26	gold quality
amygdala	UBERON:0001876	73.80	gold quality
mucosa of paranasal sinus	UBERON:0005030	73.45	gold quality
primary visual cortex	UBERON:0002436	73.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.17
E-ANND-3	yes	7.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting SPEF1, 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-4779	99.86	66.50	1583
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-4486	96.96	60.61	931
HSA-MIR-4508	90.37	59.62	240

Literature-anchored findings (GeneRIF, showing 3)

• a.k.a. Spef1 (sperm flagella) and CLAMP (CaLponin-homology And Microtubule associated Protein) CLAMP/Spef1 expression also in brain, lung, and inner ear MT association of CLAMP requires the CH domain, which has highest similarity with EB family proteins (PMID:16206169)
• Sperm flagellar 1 (also called CLAMP) is an actin-binding protein, rather than a microtubule-binding protein, in intestinal epithelial cells (IECs). CLAMP distribution changes during intestinal epithelial cell polarization, regulates the formation of filopodia, and appears to assist in the organization of actin bundles within lamellipodia of migrating IECs. (PMID:31473225)
• Spef1/CLAMP binds microtubules and actin-based structures and regulates cell migration and epithelia cell polarity. (PMID:35710871)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spef1	ENSDARG00000022007
mus_musculus	Spef1	ENSMUSG00000027329
rattus_norvegicus	LOC103691261	ENSRNOG00000036648

Paralogs (1): SPATA4 (ENSG00000150628)

Protein

Protein identifiers

Sperm flagellar protein 1 — Q9Y4P9 (reviewed: Q9Y4P9)

All UniProt accessions (1): Q9Y4P9

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule-associated protein involved in the stabilization of microtubules along the axis of migration during radial intercalation. Promotes the establishment and stabilization of an axis of microtubules required for the active migration of cells into the outer epithelium. Microtubule-associated protein that promotes microtubule bundling and stabilizes microtubules against depolymerization in response to cold shock. Essential for ciliary central apparatus formation which requires both its microtubule-binding and bundling activities and for ciliary localization of HYDIN and SPAG6 in ependymal cilia. Binds actin in intestinal epithelial cells (IECs), essential for IECs survival and contributes to formation of filopodia and lamellipodia in migrating IECs. Regulates planar cell polarity signaling pathway and asymmetric microtubule accumulation in ciliated epithelia.

Subunit / interactions. Homodimer. Interacts with actin, TJP1, CGN and CDH1.

Subcellular location. Cytoplasm. Cell projection. Cilium. Flagellum. Cytoskeleton. Cilium axoneme. Apical cell membrane. Basolateral cell membrane. Stress fiber. Microvillus. Lamellipodium. Filopodium.

Tissue specificity. Expressed in the intestinal epithelial cells (at protein level).

Domain organisation. The Calponin-homology domain mediates its binding to microtubules.

Miscellaneous. Radial intercalation is a developmentally reiterated form of migration by which cells move in a direction orthogonal to the plane of the tissue from an inner layer to an outer layer.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4P9-1	1	yes
Q9Y4P9-2	2

RefSeq proteins (1): NP_056232* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR010441	CH_2	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR052111	Spermatogenesis_Ciliary_MAP	Family

Pfam: PF06294

UniProt features (15 total): helix 7, turn 2, region of interest 2, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9NTM	ELECTRON MICROSCOPY	7.1
2EE7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4P9-F1	78.89	0.47

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 207 (showing top): MORF_RAGE, RRAGTTGT_UNKNOWN, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GGGNRMNNYCAT_UNKNOWN, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, AACYNNNNTTCCS_UNKNOWN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, AACWWCAANK_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, CAGCAGG_MIR370, GOBP_MICROTUBULE_DEPOLYMERIZATION

GO Biological Process (10): microtubule bundle formation (GO:0001578), cilium movement (GO:0003341), negative regulation of microtubule depolymerization (GO:0007026), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), filopodium assembly (GO:0046847), regulation of cytoskeleton organization (GO:0051493), axonemal central apparatus assembly (GO:1904158), regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000095), cell projection organization (GO:0030030)

GO Molecular Function (4): actin binding (GO:0003779), microtubule binding (GO:0008017), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (19): stress fiber (GO:0001725), cytoplasm (GO:0005737), microtubule (GO:0005874), microvillus (GO:0005902), axoneme (GO:0005930), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), filopodium (GO:0030175), ciliary tip (GO:0097542), 9+2 motile cilium (GO:0097729), axonemal central apparatus (GO:1990716), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cilium (GO:0005929), membrane (GO:0016020), motile cilium (GO:0031514), cell projection (GO:0042995), plasma membrane bounded cell projection (GO:0120025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
plasma membrane region	3
plasma membrane bounded cell projection assembly	2
actin-based cell projection	2
plasma membrane bounded cell projection	2
cilium	2
microtubule cytoskeleton organization	1
microtubule-based movement	1
microtubule depolymerization	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
negative regulation of protein depolymerization	1
negative regulation of supramolecular fiber organization	1
cell motility	1
lamellipodium organization	1
cytoskeleton organization	1
regulation of organelle organization	1
cellular component assembly	1
axoneme assembly	1
Wnt signaling pathway, planar cell polarity pathway	1
regulation of non-canonical Wnt signaling pathway	1
cellular component organization	1
cytoskeletal protein binding	1
tubulin binding	1
binding	1
protein binding	1
actomyosin	1
contractile actin filament bundle	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
actin filament bundle	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
basal plasma membrane	1
apical part of cell	1
cell leading edge	1
radial spoke	1
motile cilium	1

Protein interactions and networks

STRING

1301 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPEF1	MAPRE3	Q9UPY8	868
SPEF1	MAPRE1	Q15691	809
SPEF1	CNN1	P51911	764
SPEF1	SPEF2	Q9C093	616
SPEF1	SPAG6	O75602	596
SPEF1	CFAP70	Q5T0N1	488
SPEF1	SPAG16	Q8N0X2	479
SPEF1	SMOX	Q9NWM0	451
SPEF1	TSNAXIP1	Q2TAA8	431
SPEF1	ZNF567	Q8N184	430
SPEF1	HYDIN	Q4G0P3	421
SPEF1	VMO1	Q7Z5L0	406
SPEF1	C17orf107	Q6ZR85	406
SPEF1	TEX26	Q8N6G2	393
SPEF1	N4BP3	O15049	390

IntAct

9 interactions, top by confidence:

A	B	Type	Score
KLHL12	KLHL2	psi-mi:“MI:0914”(association)	0.850
KRT40	SPEF1	psi-mi:“MI:0915”(physical association)	0.560
SPEF1	ZBED1	psi-mi:“MI:0914”(association)	0.550
ZBED1	SPEF1	psi-mi:“MI:0915”(physical association)	0.550
CFTR	SPEF1	psi-mi:“MI:0915”(physical association)	0.370
SPEF1	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.370
SPEF1	VPS13B	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): KRT40 (Two-hybrid), SPEF1 (Two-hybrid), PLEKHF2 (Two-hybrid), PLEKHF2 (Two-hybrid), KRTAP13-2 (Two-hybrid), CYSRT1 (Two-hybrid), ZBED1 (Affinity Capture-MS), VPS13B (Affinity Capture-MS), WRAP73 (Affinity Capture-MS), SPEF1 (PCA)

ESM2 similar proteins: A0JMA8, A1A5P5, A2RVA7, B0S6J3, D2KC46, D3ZY60, E7F187, F1MS15, O43295, O60308, O94868, Q05B30, Q08CX1, Q08DB0, Q0IH24, Q10113, Q15057, Q17AF4, Q2KI89, Q39238, Q3B7T8, Q3USJ8, Q4R7I0, Q567U6, Q58DA1, Q5BJT7, Q5FVC7, Q5R629, Q5TZ80, Q5U245, Q5W7F2, Q5ZJ27, Q5ZK62, Q6IVG4, Q6NRB0, Q6ZQK5, Q7Z3E5, Q8BHR2, Q8BIL5, Q8RW96

Diamond homologs: Q0IH24, Q58DA1, Q6DMN8, Q8K3V1, Q8NEY3, Q99JL1, Q9Y4P9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1087 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3778415:CCTCA:C	donor_loss	1.0000
20:3778416:CTCAC:C	donor_loss	1.0000
20:3778417:TCAC:T	donor_loss	1.0000
20:3778418:CACC:C	donor_loss	1.0000
20:3778419:A:AC	donor_gain	1.0000
20:3778419:A:C	donor_loss	1.0000
20:3778420:C:CC	donor_gain	1.0000
20:3778540:CCCAG:C	acceptor_gain	1.0000
20:3778541:CCAG:C	acceptor_gain	1.0000
20:3778541:CCAGC:C	acceptor_gain	1.0000
20:3778542:CAG:C	acceptor_gain	1.0000
20:3778542:CAGC:C	acceptor_gain	1.0000
20:3778543:AG:A	acceptor_gain	1.0000
20:3778544:GC:G	acceptor_loss	1.0000
20:3778545:C:CC	acceptor_gain	1.0000
20:3779191:GGCAC:G	donor_loss	1.0000
20:3779192:GCAC:G	donor_loss	1.0000
20:3779193:CACC:C	donor_loss	1.0000
20:3779212:C:CA	donor_gain	1.0000
20:3779219:T:TA	donor_gain	1.0000
20:3779324:C:CC	acceptor_gain	1.0000
20:3779353:CTGA:C	acceptor_loss	1.0000
20:3779354:T:A	acceptor_loss	1.0000
20:3778318:ACCTA:A	acceptor_loss	0.9900
20:3778319:CCTAA:C	acceptor_loss	0.9900
20:3778420:CCTG:C	donor_gain	0.9900
20:3778543:A:T	acceptor_gain	0.9900
20:3778947:TTA:T	donor_loss	0.9900
20:3778948:TA:T	donor_loss	0.9900
20:3778949:A:AC	donor_gain	0.9900

AlphaMissense

1534 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3779680:A:G	W69R	0.998
20:3779680:A:T	W69R	0.998
20:3778272:C:A	K217N	0.996
20:3778272:C:G	K217N	0.996
20:3779681:G:C	N68K	0.996
20:3779681:G:T	N68K	0.996
20:3781181:C:T	G36E	0.996
20:3778285:A:G	L213P	0.995
20:3779670:A:G	L72P	0.995
20:3779678:C:A	W69C	0.995
20:3779678:C:G	W69C	0.995
20:3781190:A:G	F33S	0.995
20:3781186:G:C	S34R	0.994
20:3781186:G:T	S34R	0.994
20:3781188:T:G	S34R	0.994
20:3778276:A:G	L216P	0.993
20:3778282:A:G	L214P	0.993
20:3779263:A:T	L104H	0.993
20:3779679:C:G	W69S	0.993
20:3779766:G:T	A40E	0.993
20:3781242:A:G	W16R	0.993
20:3781242:A:T	W16R	0.993
20:3779690:C:A	K65N	0.992
20:3779690:C:G	K65N	0.992
20:3779692:T:C	K65E	0.992
20:3781182:C:G	G36R	0.992
20:3781182:C:T	G36R	0.992
20:3781196:C:G	R31P	0.992
20:3781210:C:A	K26N	0.992
20:3781210:C:G	K26N	0.992

dbSNP variants (sampled 300 via entrez): RS1000082027 (20:3783217 G>A), RS1000947623 (20:3781791 C>T), RS1001121997 (20:3777678 CG>C), RS1001508296 (20:3777958 A>C,G), RS1002144633 (20:3779358 G>A,T), RS1002213908 (20:3780997 A>G), RS1002578923 (20:3779067 C>G,T), RS1002812506 (20:3782477 G>C,T), RS1003584379 (20:3779577 G>T), RS1004853939 (20:3777240 G>T), RS1004991080 (20:3777588 A>C), RS1005741446 (20:3779718 T>A,C), RS1006643999 (20:3781807 C>A,T), RS1007193242 (20:3782149 C>T), RS1007332088 (20:3782327 T>C)

Disease associations

OMIM: gene MIM:610674 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003075_23	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST003075_62	Cognitive decline rate in late mild cognitive impairment	7.000000e-07
GCST006134_12	Hippocampal volume	6.000000e-06
GCST90002389_415	Lymphocyte percentage of white cells	5.000000e-13
GCST90002399_447	Neutrophil percentage of white cells	8.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0005035	hippocampal volume
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

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
Air Pollutants	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
versicolorin A	increases expression	1
pentanal	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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