CFAP276

Summary

CFAP276 (cilia and flagella associated protein 276, HGNC:32331) is a protein-coding gene on chromosome 1p13.3, encoding Cilia- and flagella-associated protein 276 (Q5T5A4). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

Predicted to be involved in flagellated sperm motility. Located in axonemal microtubule.

Source: NCBI Gene 127003 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_001245025

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32331
Approved symbol	CFAP276
Name	cilia and flagella associated protein 276
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000179902
Ensembl biotype	protein_coding
OMIM	618682
Entrez	127003

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000369942, ENST00000369945, ENST00000369948, ENST00000369949, ENST00000460065, ENST00000462402, ENST00000866707

RefSeq mRNA: 5 — MANE Select: NM_001245025 NM_001122961, NM_001245025, NM_001366200, NM_001366201, NM_001366202

CCDS: CCDS41364, CCDS91015, CCDS91016

Canonical transcript exons

ENST00000369948 — 5 exons

Exon	Start	End
ENSE00001451301	109112599	109112747
ENSE00001623202	109107007	109107122
ENSE00003570229	109107921	109108037
ENSE00003580269	109105951	109106098
ENSE00003676093	109106535	109106659

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 99.74.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2064 / max 475.4436, expressed in 248 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13672	0.9574	176
13673	0.5521	109
13676	0.4466	78
13675	0.1303	11
13674	0.0961	33
13671	0.0239	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.74	gold quality
bronchial epithelial cell	CL:0002328	99.16	gold quality
left testis	UBERON:0004533	98.67	gold quality
sperm	CL:0000019	98.64	gold quality
right testis	UBERON:0004534	98.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.15	gold quality
bronchus	UBERON:0002185	97.94	gold quality
oviduct epithelium	UBERON:0004804	96.54	gold quality
testis	UBERON:0000473	95.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.37	gold quality
fallopian tube	UBERON:0003889	92.22	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.37	gold quality
adult organism	UBERON:0007023	91.36	gold quality
nasal cavity epithelium	UBERON:0005384	89.48	gold quality
caudate nucleus	UBERON:0001873	88.25	gold quality
nucleus accumbens	UBERON:0001882	87.49	gold quality
right lung	UBERON:0002167	86.05	gold quality
epithelium of nasopharynx	UBERON:0001951	85.73	silver quality
hypothalamus	UBERON:0001898	84.42	gold quality
putamen	UBERON:0001874	84.10	gold quality
pituitary gland	UBERON:0000007	83.01	gold quality
adenohypophysis	UBERON:0002196	82.90	gold quality
amygdala	UBERON:0001876	82.52	gold quality
anterior cingulate cortex	UBERON:0009835	80.45	gold quality
nasal cavity mucosa	UBERON:0001826	80.35	gold quality
ventricular zone	UBERON:0003053	79.70	gold quality
prefrontal cortex	UBERON:0000451	79.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.82	gold quality
right frontal lobe	UBERON:0002810	78.67	gold quality
left uterine tube	UBERON:0001303	78.10	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	2898.10
E-HCAD-1	yes	2074.39
E-MTAB-8221	yes	1982.56
E-MTAB-6701	yes	1746.34
E-CURD-114	yes	1715.18
E-GEOD-130148	yes	1515.30
E-HCAD-38	yes	1465.50
E-MTAB-10287	yes	1413.14
E-MTAB-9154	yes	1298.27
E-MTAB-10485	yes	560.17
E-GEOD-134144	yes	30.60
E-MTAB-9388	yes	7.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• the identification of two heterozygous missense mutations in the C1orf194 gene at 1p21.2-p13.2 with Charcot-Marie-Tooth disease are reported (PMID:31199454)
• C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model. (PMID:32592472)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-163l21.7	ENSDARG00000034457
mus_musculus	Cfap276	ENSMUSG00000027886
rattus_norvegicus	Cfap276	ENSRNOG00000020307

Paralogs (4): FLVCR2 (ENSG00000119686), SLC49A4 (ENSG00000138463), FLVCR1 (ENSG00000162769), SLC49A3 (ENSG00000169026)

Protein

Protein identifiers

Cilia- and flagella-associated protein 276 — Q5T5A4 (reviewed: Q5T5A4)

All UniProt accessions (4): B1ALJ5, E9PLX1, E9PRR4, Q5T5A4

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. May play an important role for the maintenance of myelin-axon integrity. May affect intracellular Ca(2+) homeostasis.

Subunit / interactions. Microtubule inner protein component of sperm flagellar doublet microtubules.

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

Tissue specificity. Expressed in cerebrum, cerebellum, gastrocnemius muscle, spinal cord and lung tissues.

Disease relevance. CFAP276 mutations may be the cause of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. Intermediate forms of Charcot-Marie-Tooth disease exist and are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5T5A4-1	1	yes
Q5T5A4-2	2

RefSeq proteins (5): NP_001116433, NP_001231954, NP_001353129, NP_001353130, NP_001353131 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022179	CFAP276	Family

Pfam: PF12494

UniProt features (8 total): region of interest 2, compositionally biased region 2, sequence variant 2, chain 1, splice variant 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-Q5T5A4-F1	67.55	0.03

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): BENPORATH_ES_WITH_H3K27ME3, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOCC_CYTOPLASMIC_REGION, GOCC_MOTILE_CILIUM, GOCC_CYTOPLASMIC_MICROTUBULE, GOCC_CILIUM, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOCC_AXONEMAL_MICROTUBULE, GOCC_9PLUS2_MOTILE_CILIUM, GOCC_SUPRAMOLECULAR_COMPLEX, GOCC_POLYMERIC_CYTOSKELETAL_FIBER, GOCC_SUPRAMOLECULAR_POLYMER, FOXJ2_TARGET_GENES

GO Biological Process (1): flagellated sperm motility (GO:0030317)

GO Molecular Function (0):

GO Cellular Component (8): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), axonemal microtubule (GO:0005879), sperm flagellum (GO:0036126), axonemal B tubule inner sheath (GO:0160112), 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
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cytoplasmic microtubule	1
axoneme	1
9+2 motile cilium	1
A axonemal microtubule	1
axonemal microtubule doublet inner sheath	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFAP276	UQCR10	Q9UDW1	646
CFAP276	SPACA7	Q96KW9	507
CFAP276	CLCC1	Q96S66	505
CFAP276	VWA8	A3KMH1	501
CFAP276	BOD1L2	Q8IYS8	478
CFAP276	NEK10	Q6ZWH5	471
CFAP276	TMEM167B	Q9NRX6	462
CFAP276	CCDC89	Q8N998	447
CFAP276	AKNAD1	Q5T1N1	438
CFAP276	SPACDR	Q8IZ16	418
CFAP276	PHF7	Q9BWX1	418
CFAP276	OR7G2	Q8NG99	415
CFAP276	MFSD6L	Q8IWD5	396
CFAP276	ZNF880	Q6PDB4	392
CFAP276	WDR47	O94967	377

IntAct

0 interactions, top by confidence:

BioGRID (1): C1orf194 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GU33, A0A1B0GUV7, A0A1L8FZ84, A4GZ95, A6ZT44, A8MTZ7, E1B9I5, G1XTZ6, P03562, P05909, P05910, P05911, P0C6G2, P0C6G4, P0C6G5, P0CK37, P0CK38, P12513, P14968, P21740, P26548, P27262, P27263, P27271, P32645, P33199, P36280, P38612, P43580, P87318, Q03937, Q09824, Q1A264, Q2V2P0, Q3KPS4, Q5T5A4, Q5T7R7, Q67621, Q6W0C5, Q88891

Diamond homologs: A8Y5T1, E1B9I5, Q5T5A4, Q9DAD0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

394 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109106097:CA:C	acceptor_gain	1.0000
1:109106099:C:CC	acceptor_gain	1.0000
1:109106531:TTA:T	donor_loss	1.0000
1:109106660:C:CC	acceptor_gain	1.0000
1:109106671:C:CT	acceptor_gain	1.0000
1:109106094:GGACA:G	acceptor_gain	0.9900
1:109106095:GACA:G	acceptor_gain	0.9900
1:109106099:C:CA	acceptor_loss	0.9900
1:109106100:T:C	acceptor_loss	0.9900
1:109106101:G:C	acceptor_gain	0.9900
1:109106533:A:AC	donor_gain	0.9900
1:109106534:C:CC	donor_gain	0.9900
1:109106655:TGGTT:T	acceptor_gain	0.9900
1:109106658:TT:T	acceptor_gain	0.9900
1:109106660:C:A	acceptor_loss	0.9900
1:109106672:A:AC	acceptor_gain	0.9900
1:109106672:A:C	acceptor_gain	0.9900
1:109106672:A:T	acceptor_gain	0.9900
1:109106096:ACA:A	acceptor_gain	0.9800
1:109106097:CAC:C	acceptor_gain	0.9800
1:109106528:CCCTT:C	donor_gain	0.9800
1:109106531:TTACC:T	donor_gain	0.9800
1:109106532:TACCT:T	donor_gain	0.9800
1:109106533:ACCTA:A	donor_gain	0.9800
1:109106534:CCTAT:C	donor_gain	0.9800
1:109106656:GGTT:G	acceptor_gain	0.9800
1:109106657:GTT:G	acceptor_gain	0.9800
1:109108709:A:C	donor_gain	0.9800
1:109106101:G:GC	acceptor_gain	0.9700
1:109106529:CCTTA:C	donor_gain	0.9700

AlphaMissense

1106 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:109106037:G:C	F167L	0.979
1:109106037:G:T	F167L	0.979
1:109106039:A:G	F167L	0.979
1:109106059:C:G	R160P	0.967
1:109106040:G:C	F166L	0.946
1:109106040:G:T	F166L	0.946
1:109106042:A:G	F166L	0.946
1:109106066:A:C	Y158D	0.944
1:109106088:G:C	H150Q	0.941
1:109106088:G:T	H150Q	0.941
1:109106583:A:G	W131R	0.934
1:109106583:A:T	W131R	0.934
1:109107989:A:G	W44R	0.933
1:109107989:A:T	W44R	0.933
1:109106090:G:C	H150D	0.930
1:109107106:A:G	L72P	0.920
1:109106060:G:C	R160G	0.918
1:109106068:C:T	G157D	0.918
1:109106065:T:G	Y158S	0.915
1:109107094:A:G	L76S	0.915
1:109107113:C:G	D70H	0.913
1:109106038:A:G	F167S	0.906
1:109106047:C:A	G164V	0.900
1:109106063:A:G	S159P	0.900
1:109106077:G:A	T154I	0.899
1:109106069:C:G	G157R	0.897
1:109106055:C:A	K161N	0.888
1:109106055:C:G	K161N	0.888
1:109106537:A:T	I146K	0.887
1:109106038:A:C	F167C	0.885

dbSNP variants (sampled 300 via entrez): RS1000298997 (1:109105868 C>A,T), RS1000704087 (1:109115652 TA>T), RS1000957356 (1:109114064 G>C), RS1001108653 (1:109113684 T>A), RS1001218149 (1:109112685 A>G), RS1001768590 (1:109105611 G>A), RS1001861864 (1:109108829 T>C), RS1002004001 (1:109115232 T>A), RS1002516861 (1:109114960 C>T), RS1002621587 (1:109110912 G>C), RS1002830891 (1:109113926 G>A,C), RS1002865093 (1:109110400 T>A), RS1002896326 (1:109110101 C>T), RS1002953543 (1:109113639 C>A,G,T), RS1003863865 (1:109107417 T>A,C)

Disease associations

OMIM: gene MIM:618682 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Limited	Autosomal dominant

Mondo (1): Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90011900_51	Serum alkaline phosphatase levels	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aflatoxin B2	decreases methylation	1
tebuconazole	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT