CFAP69

Summary

CFAP69 (cilia and flagella associated protein 69, HGNC:26107) is a protein-coding gene on chromosome 7q21.13, encoding Cilia- and flagella-associated protein 69 (A5D8W1). Cilium- and flagellum-associated protein.

Acts upstream of or within sperm axoneme assembly. Located in cytoplasm and sperm midpiece. Implicated in spermatogenic failure 24.

Source: NCBI Gene 79846 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic male infertility due to sperm motility disorder (Supportive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 189 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_001039706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26107
Approved symbol	CFAP69
Name	cilia and flagella associated protein 69
Location	7q21.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21062, FAP69
Ensembl gene	ENSG00000105792
Ensembl biotype	protein_coding
OMIM	617949
Entrez	79846

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000389297, ENST00000412839, ENST00000418199, ENST00000427396, ENST00000445156, ENST00000449577, ENST00000451029, ENST00000457170, ENST00000463311, ENST00000475031, ENST00000485791, ENST00000491886, ENST00000497910, ENST00000867384, ENST00000867385, ENST00000949772, ENST00000949773, ENST00000949774, ENST00000949775

RefSeq mRNA: 3 — MANE Select: NM_001039706 NM_001039706, NM_001160138, NM_001363438

CCDS: CCDS43613, CCDS55122

Canonical transcript exons

ENST00000389297 — 23 exons

Exon	Start	End
ENSE00001336059	90261947	90262056
ENSE00001879436	90245174	90245544
ENSE00001957311	90310068	90311063
ENSE00003464437	90265301	90265377
ENSE00003468927	90299867	90300059
ENSE00003469694	90282892	90283056
ENSE00003492135	90271781	90271958
ENSE00003500406	90255423	90255482
ENSE00003527330	90303969	90304106
ENSE00003552838	90268286	90268384
ENSE00003560031	90297749	90297830
ENSE00003561841	90279677	90279893
ENSE00003582822	90277073	90277121
ENSE00003590670	90258098	90258163
ENSE00003595006	90309263	90309367
ENSE00003602008	90271526	90271675
ENSE00003619891	90306901	90307098
ENSE00003621021	90277213	90277334
ENSE00003631849	90288234	90288352
ENSE00003633681	90304744	90304820
ENSE00003637715	90273987	90274110
ENSE00003640776	90286281	90286399
ENSE00003690139	90307768	90307854

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.62.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9901 / max 48.4918, expressed in 876 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79444	0.6001	330
79447	0.3865	220
79443	0.3795	191
79446	0.3556	186
79445	0.2637	135
79442	0.0047	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.62	gold quality
bronchial epithelial cell	CL:0002328	95.88	gold quality
epithelium of bronchus	UBERON:0002031	95.24	gold quality
bronchus	UBERON:0002185	94.58	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.71	gold quality
calcaneal tendon	UBERON:0003701	91.46	gold quality
caput epididymis	UBERON:0004358	91.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.91	gold quality
prostate gland	UBERON:0002367	88.39	gold quality
sperm	CL:0000019	86.71	gold quality
choroid plexus epithelium	UBERON:0003911	86.44	gold quality
tendon	UBERON:0000043	85.92	gold quality
adenohypophysis	UBERON:0002196	85.67	gold quality
male germ cell	CL:0000015	85.52	gold quality
pituitary gland	UBERON:0000007	85.21	gold quality
corpus epididymis	UBERON:0004359	84.49	gold quality
left lobe of thyroid gland	UBERON:0001120	84.08	gold quality
thyroid gland	UBERON:0002046	83.69	gold quality
tibial nerve	UBERON:0001323	83.65	gold quality
right lobe of thyroid gland	UBERON:0001119	82.93	gold quality
nasal cavity epithelium	UBERON:0005384	82.45	silver quality
tendon of biceps brachii	UBERON:0008188	82.06	gold quality
fallopian tube	UBERON:0003889	81.77	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.68	gold quality
mucosa of stomach	UBERON:0001199	81.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.45	gold quality
metanephros cortex	UBERON:0010533	81.34	gold quality
endocervix	UBERON:0000458	81.22	gold quality
left ovary	UBERON:0002119	81.00	gold quality
nasal cavity mucosa	UBERON:0001826	80.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	545.06
E-ANND-3	yes	9.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting CFAP69, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-6831-3P	97.49	69.29	505
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-4540	96.90	67.46	473
HSA-MIR-4296	96.35	63.55	1233

Literature-anchored findings (GeneRIF, showing 4)

• A CpG island proximal to FLJ21062 is frequently methylated in diffuse large B-cell lymphoma (DLBCL). (PMID:18288132)
• CFAP69 is necessary for flagellum assembly/stability and that in both humans and mice (PMID:29606301)
• Homozygous loss-of-function mutations of CFAP69 are associated with abnormalities of the sperm flagella and severe asthenoteratospermia. (PMID:30415212)
• A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review. (PMID:37392306)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cfap69	ENSMUSG00000040473
rattus_norvegicus	Cfap69	ENSRNOG00000006114

Protein

Protein identifiers

Cilia- and flagella-associated protein 69 — A5D8W1 (reviewed: A5D8W1)

All UniProt accessions (7): A5D8W1, F8WBX7, H7BZV2, H7C002, H7C076, H7C3Z7, H7C468

UniProt curated annotations — full annotation on UniProt →

Function. Cilium- and flagellum-associated protein. In the olfactory epithelium, regulates the speed of activation and termination of the odor response and thus contributes to the robustness of olfactory transduction pathways. Required for sperm flagellum assembly and stability.

Subcellular location. Cell projection. Cilium. Flagellum.

Tissue specificity. Highly expressed in the testis, specifically in sperm (at protein level). Expressed in the brain, kidney, liver, lung, and intestine.

Disease relevance. Spermatogenic failure 24 (SPGF24) [MIM:617959] An autosomal recessive infertility disorder caused by spermatogenesis defects that result in multiple morphologic abnormalities of the flagella, including absent, short, coiled, bent, and irregular-caliber flagella. Malformations of the sperm head have also been observed. In addition, patients exhibit very low sperm concentrations and total sperm counts per ejaculate. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Incomplete sequence.

Isoforms (5)

UniProt ID	Names	Canonical?
A5D8W1-1	1	yes
A5D8W1-2	2
A5D8W1-3	3
A5D8W1-4	4
A5D8W1-5	5

RefSeq proteins (3): NP_001034795, NP_001153610, NP_001350367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR048732	CFA69	Family
IPR048733	CFA69_ARM_dom	Domain

Pfam: PF21049

UniProt features (19 total): sequence variant 6, splice variant 5, sequence conflict 4, compositionally biased region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A5D8W1-F1	85.48	0.62

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, NFKB_Q6, GOBP_CILIUM_ORGANIZATION, GOBP_CHEMOSENSORY_BEHAVIOR, GOBP_CILIUM_MOVEMENT, GOBP_REGULATION_OF_MICROTUBULE_BASED_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_ORGANELLE_ASSEMBLY

GO Biological Process (9): sperm axoneme assembly (GO:0007288), sensory perception of smell (GO:0007608), flagellated sperm motility (GO:0030317), olfactory behavior (GO:0042048), positive regulation of flagellated sperm motility (GO:1902093), positive regulation of fertilization (GO:1905516), response to odorant (GO:1990834), spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (6): cytoplasm (GO:0005737), sperm midpiece (GO:0097225), non-motile cilium (GO:0097730), 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
positive regulation of reproductive process	2
cilium	2
axoneme assembly	1
sperm flagellum assembly	1
sensory perception of chemical stimulus	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
chemosensory behavior	1
positive regulation of cilium movement	1
flagellated sperm motility	1
regulation of flagellated sperm motility	1
positive regulation of cilium-dependent cell motility	1
fertilization	1
regulation of fertilization	1
response to chemical	1
male gamete generation	1
cellular developmental process	1
intracellular anatomical structure	1
sperm flagellum	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFAP69	CFAP44	Q96MT7	786
CFAP69	CFAP43	Q8NDM7	781
CFAP69	CFAP251	Q8TBY9	715
CFAP69	QRICH2	Q9H0J4	706
CFAP69	DNAH1	Q9P2D7	701
CFAP69	ARMC2	Q8NEN0	670
CFAP69	SPEF2	Q9C093	668
CFAP69	CFAP70	Q5T0N1	663
CFAP69	TTC21A	Q8NDW8	646
CFAP69	FSIP2	Q5CZC0	640
CFAP69	TTC29	Q8NA56	627
CFAP69	CFAP91	Q7Z4T9	602
CFAP69	DNAH17	Q9UFH2	584
CFAP69	AK7	Q96M32	583
CFAP69	CFAP58	Q5T655	582

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CFAP69	SEPTIN1	psi-mi:“MI:0915”(physical association)	0.400
P		psi-mi:“MI:0914”(association)	0.350
ADGRG2	CFAP69	psi-mi:“MI:0914”(association)	0.350
CFAP69	UTRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): CFAP69 (Affinity Capture-RNA), SEPT1 (Proximity Label-MS), SNTA1 (Affinity Capture-MS), UTRN (Affinity Capture-MS), B3GALNT2 (Affinity Capture-MS), CFAP69 (Affinity Capture-MS), BSG (Cross-Linking-MS (XL-MS)), CFAP69 (Cross-Linking-MS (XL-MS)), ATP5B (Cross-Linking-MS (XL-MS)), CFAP69 (Affinity Capture-MS)

ESM2 similar proteins: A1Z8X3, A2RT91, A5D8W1, A6NKT7, B0CM26, B0VXE6, B1WBT0, C9JQI7, F4JY37, G5ED39, H2QII6, O01510, O08662, O14715, O43065, O94324, P0DJD0, P0DJD1, P12798, P32333, P40955, P45964, P49792, Q01015, Q03280, Q03569, Q0IEK6, Q10122, Q13535, Q17551, Q177G4, Q18508, Q21920, Q4UKJ5, Q5K6N0, Q5S007, Q60J38, Q70PP2, Q756G2, Q7TSH2

Diamond homologs: A5D8W1, B0CM26, B0VXE6, Q8BH53

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	127
Likely benign	20
Benign	14

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
523226	NM_001039706.3(CFAP69):c.860+1G>A	Pathogenic
523227	NM_001039706.3(CFAP69):c.763C>T (p.Gln255Ter)	Pathogenic
626908	NM_001039706.3(CFAP69):c.1069_1070insAC (p.Leu357fs)	Pathogenic
626909	NM_001039706.3(CFAP69):c.647G>A (p.Trp216Ter)	Pathogenic
3256949	NM_001039706.3(CFAP69):c.340_341del (p.Ile114fs)	Likely pathogenic
3779058	NM_001039706.3(CFAP69):c.2602C>T (p.Arg868Ter)	Likely pathogenic

SpliceAI

3773 predictions. Top by Δscore:

Variant	Effect	Δscore
7:90245544:GGTA:G	donor_loss	1.0000
7:90245545:G:GC	donor_loss	1.0000
7:90271674:TGGT:T	donor_loss	1.0000
7:90271675:GG:G	donor_loss	1.0000
7:90271676:GTTT:G	donor_loss	1.0000
7:90271677:T:A	donor_loss	1.0000
7:90271921:G:GT	donor_gain	1.0000
7:90271935:GCTTA:G	donor_gain	1.0000
7:90271936:C:G	donor_gain	1.0000
7:90271956:GCT:G	donor_gain	1.0000
7:90271963:GC:G	donor_gain	1.0000
7:90273981:TTCTA:T	acceptor_loss	1.0000
7:90273982:TCTAG:T	acceptor_loss	1.0000
7:90273983:CTAGG:C	acceptor_loss	1.0000
7:90273984:TA:T	acceptor_loss	1.0000
7:90273985:A:C	acceptor_loss	1.0000
7:90273986:G:A	acceptor_loss	1.0000
7:90274107:GATT:G	donor_gain	1.0000
7:90274111:G:GG	donor_gain	1.0000
7:90279672:CACAG:C	acceptor_loss	1.0000
7:90279673:A:AG	acceptor_gain	1.0000
7:90279674:C:G	acceptor_gain	1.0000
7:90279674:CAGCT:C	acceptor_loss	1.0000
7:90279675:A:AG	acceptor_gain	1.0000
7:90279676:G:GA	acceptor_gain	1.0000
7:90279676:GC:G	acceptor_gain	1.0000
7:90279676:GCT:G	acceptor_gain	1.0000
7:90279676:GCTA:G	acceptor_gain	1.0000
7:90279676:GCTAT:G	acceptor_gain	1.0000
7:90279718:T:G	acceptor_gain	1.0000

AlphaMissense

6229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:90300002:T:A	W665R	0.996
7:90300002:T:C	W665R	0.996
7:90279788:G:C	A423P	0.995
7:90279783:T:C	L421P	0.992
7:90271891:T:A	W265R	0.991
7:90271891:T:C	W265R	0.991
7:90274049:T:C	L308P	0.991
7:90274056:T:A	N310K	0.990
7:90274056:T:G	N310K	0.990
7:90299954:T:A	W649R	0.990
7:90299954:T:C	W649R	0.990
7:90304820:A:C	K755N	0.989
7:90304820:A:T	K755N	0.989
7:90271664:T:C	L224P	0.988
7:90277288:T:C	L370P	0.988
7:90304075:A:C	R719S	0.986
7:90304075:A:T	R719S	0.986
7:90274058:A:C	D311A	0.985
7:90277266:G:C	D363H	0.985
7:90279789:C:A	A423E	0.984
7:90304789:T:C	L745P	0.984
7:90271655:T:C	L221P	0.983
7:90277107:C:A	A340D	0.983
7:90274053:A:C	R309S	0.982
7:90274053:A:T	R309S	0.982
7:90300004:G:C	W665C	0.982
7:90300004:G:T	W665C	0.982
7:90304798:T:A	I748K	0.982
7:90271886:T:A	I263K	0.980
7:90271937:T:C	L280P	0.980

dbSNP variants (sampled 300 via entrez): RS1000004670 (7:90271045 G>C), RS1000027284 (7:90282372 C>T), RS1000094082 (7:90289040 T>A), RS1000200912 (7:90310977 A>T), RS1000220488 (7:90272678 G>A,C), RS1000227628 (7:90307306 C>T), RS1000260616 (7:90268643 T>A), RS1000275660 (7:90261275 A>G), RS1000305035 (7:90251963 C>A), RS1000441773 (7:90252315 T>C,G), RS1000443380 (7:90319550 T>G), RS1000466255 (7:90289286 G>T), RS1000521286 (7:90294156 A>C), RS1000552154 (7:90280105 G>A), RS1000559713 (7:90247852 A>G)

Disease associations

OMIM: gene MIM:617949 | disease phenotypes: MIM:617959

GenCC curated gene-disease

Disease	Classification	Inheritance
non-syndromic male infertility due to sperm motility disorder	Supportive	Autosomal recessive
spermatogenic failure 24	Limited	Autosomal recessive

Mondo (2): spermatogenic failure 24 (MONDO:0054728), (MONDO:0017173)

Orphanet (1): Non-syndromic male infertility due to sperm motility disorder (Orphanet:276234)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0012207	Reduced sperm motility
HP:0032559	Short sperm flagella
HP:0032560	Coiled sperm flagella
HP:0032561	Microcephalic sperm head
HP:0032562	Tapered sperm head

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

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
bisphenol A	decreases expression, affects cotreatment, increases methylation	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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