DNAAF4

Summary

DNAAF4 (dynein axonemal assembly factor 4, HGNC:21493) is a protein-coding gene on chromosome 15q21.3, encoding Dynein axonemal assembly factor 4 (Q8WXU2). Axonemal dynein assembly factor required for ciliary motility.

This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene.

Source: NCBI Gene 161582 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ciliary dyskinesia 25 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 321 total — 33 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 64
• MANE Select transcript: NM_130810

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21493
Approved symbol	DNAAF4
Name	dynein axonemal assembly factor 4
Location	15q21.3
Locus type	gene with protein product
Status	Approved
Aliases	EKN1, FLJ37882, CILD25, pf23
Ensembl gene	ENSG00000256061
Ensembl biotype	protein_coding
OMIM	608706
Entrez	161582

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000321149, ENST00000348518, ENST00000448430, ENST00000457155, ENST00000519017, ENST00000522437, ENST00000524160, ENST00000866260

RefSeq mRNA: 3 — MANE Select: NM_130810 NM_001033559, NM_001033560, NM_130810

CCDS: CCDS10154, CCDS32243, CCDS32244

Canonical transcript exons

ENST00000321149 — 10 exons

Exon	Start	End
ENSE00001351946	55498207	55498584
ENSE00001351948	55508122	55508234
ENSE00003499327	55497712	55497859
ENSE00003523433	55450222	55450367
ENSE00003548321	55491123	55491256
ENSE00003561118	55434905	55435058
ENSE00003570696	55432497	55432602
ENSE00003624194	55439472	55439581
ENSE00003669778	55466930	55467161
ENSE00003676426	55430308	55430779

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 95.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7388 / max 253.7529, expressed in 1457 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150096	7.7388	1457

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	95.26	gold quality
bronchus	UBERON:0002185	93.34	gold quality
secondary oocyte	CL:0000655	87.39	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.15	gold quality
right uterine tube	UBERON:0001302	87.01	gold quality
oviduct epithelium	UBERON:0004804	84.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.11	gold quality
right lobe of thyroid gland	UBERON:0001119	82.16	gold quality
epithelium of nasopharynx	UBERON:0001951	81.70	gold quality
left lobe of thyroid gland	UBERON:0001120	81.26	gold quality
thyroid gland	UBERON:0002046	81.17	gold quality
ventricular zone	UBERON:0003053	78.54	gold quality
sural nerve	UBERON:0015488	78.12	gold quality
fallopian tube	UBERON:0003889	77.44	gold quality
sperm	CL:0000019	77.28	gold quality
caput epididymis	UBERON:0004358	76.70	gold quality
cortical plate	UBERON:0005343	75.10	gold quality
testis	UBERON:0000473	74.56	gold quality
right testis	UBERON:0004534	73.52	gold quality
adenohypophysis	UBERON:0002196	73.50	gold quality
left testis	UBERON:0004533	73.20	gold quality
islet of Langerhans	UBERON:0000006	72.93	gold quality
calcaneal tendon	UBERON:0003701	72.87	gold quality
stromal cell of endometrium	CL:0002255	71.95	gold quality
right lung	UBERON:0002167	71.30	gold quality
pituitary gland	UBERON:0000007	71.28	gold quality
ganglionic eminence	UBERON:0004023	70.88	gold quality
smooth muscle tissue	UBERON:0001135	70.73	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	28.39
E-GEOD-137537	yes	14.30
E-CURD-114	yes	11.06
E-ANND-3	yes	9.69
E-MTAB-9388	yes	6.64
E-MTAB-7303	no	109.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, GTF2I, NR1I2, PARP1, SFPQ

miRNA regulators (miRDB)

28 targeting DNAAF4, 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-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-6836-3P	97.08	64.99	712
HSA-MIR-4529-5P	96.74	65.77	569

Literature-anchored findings (GeneRIF, showing 34)

• DYX1C1 should be regarded as a candidate gene for developmental dyslexia and localizes to a fraction of cortical neurons and white matter glial cells (PMID:12954984)
• Findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. (PMID:15249932)
• Thus it seems unlikely that DYX1C1 gene would be involved in the genetic etiology of autism in Finnish patients. (PMID:15470369)
• DYX1C1 is unlikely to be a susceptibility gene for developmental dyslexia (PMID:15477871)
• Single nucleotide polymorphisms of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs. (PMID:15520411)
• Functional characterization of the homologous rat protein. (PMID:16989952)
• disequilibrium with DYX1C1 is more saliently explained in Italian dyslexics by short-term memory (PMID:17309662)
• The observation of weak evidence for transmission disequilibrium for one of the two studied polymorphisms in DYX1C1 suggests involvement of this gene in dyslexia. (PMID:17450541)
• TFII-I, PARP1, and SFPQ proteins, each previously implicated in gene regulation, form a complex controlling transcription of DYX1C1. Allelic differences in the promoter or 5’UTR of DYX1C1 may affect factor binding and thus regulation of the gene. (PMID:18445785)
• Alternatively spliced transcript variants of the DYX1C1 gene may be used as cancer biomarkers to detect colorectal cancer. (PMID:18618141)
• The contribution of DYX1C1 to dyslexia in a sample of 366 trios of German descent, was investigated. (PMID:19240663)
• The DYX1C1 is a novel Hsp70 and Hsp90-interacting co-chaperone protein and its expression is associated with malignancy. (PMID:19277710)
• DYX1C1 interacts with both ERs in the presence of 17beta-estradiol in neurons. (PMID:19423554)
• Results suggest that DYX1C1 influences reading and spelling ability with additional effects on short-term information storage or rehearsal. Missense mutation rs17819126 is a potential functional basis for the association of DYX1C1 with dyslexia. (PMID:19901951)
• As a first exploitation of this unique cohort, we identify three novel candidate dyslexia genes, ZNF280D and TCF12 at 15q21, and PDE7B at 6q23.3, by molecular mapping of the familial translocation with the 15q21 breakpoint. (PMID:20798984)
• Association signals were detected for several single nucleotide polymorphisms within DYX1C1 with both the reading and spelling tests (PMID:20846247)
• No statistically significant associations were found between DCDC2 or DYX1C1 and language phenotypes. Both DCDC2 and DYX1C1 DD susceptibility genes appear to have a pleiotropic role on mathematics but not language phenotypes. (PMID:21046216)
• At this point, there is no statistical evidence of association between the allelic variation in the three candidate genes and DD in our sample. (PMID:21203818)
• findings suggest that DYX1C1 is associated with dyslexia in people of Chinese ethnicity. (PMID:21599957)
• the expression of DYX1C1 in breast cancer is associated with several clinicopathological parameters and that loss of DYX1C1 correlates with a more aggressive disease, in turn indicating that DYX1C1 is a potential prognostic biomarker in breast cancer. (PMID:22375924)
• A single nucleotide polymorphism previously shown to be associated with dyslexia and located in the cis-regulatory region of DYX1C1 may alter the epigenetic and endocrine regulation of this gene. (PMID:22383464)
• Mutations in cilia co-expressed DCDC2, DYX1C1 and KIAA0319 genes are associated with a cognitive neurological disorder, dyslexia. (PMID:22558177)
• The results of this study found that DYX1C1 gene contained polymorphisms that were significantly associated with white matter volume in the left temporo-parietal region and that white matter volume influenced reading ability. (PMID:22683091)
• DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene. (PMID:23028439)
• results demonstrate that DYX1C1 can modulate the expression of genes involved in cell migration and nervous system development and associates with a number of cytoskeletal proteins. (PMID:23036959)
• results suggested that the 931C > T variant in KIAA0319, but not the -3G > A in DYX1C1, was significantly associated with the risk of dyslexia (PMID:23065966)
• Gene-by-environment effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio-economic status) and the DYX1C1-1259C/G marker (PMID:23176554)
• The results of this study do not provide evidence for association between the putatively functional single nucleotide polymorphisms -3G/A and 1249G/T in DYX1C1 and reading disabilities. (PMID:23341075)
• DYX1C1 is required for axonemal dynein assembly and ciliary motility. (PMID:23872636)
• promoter SNP rs12899331 of DYX1C1 may contribute towards the manifestation of DD. This study supports the association of DYX1C1 with DD in an Indian population (PMID:24362368)
• that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium (PMID:27451412)
• Novel dynein axonemal assembly factor 1 mutations identified using wholeexome sequencing in patients with primary ciliary dyskinesia. (PMID:33174003)
• A novel homozygous splice variant in DNAAF4 is associated with asthenozoospermia. (PMID:37674365)
• Developmental dyslexia susceptibility genes DNAAF4, DCDC2, and NRSN1 are associated with brain function in fluently reading adolescents and young adults. (PMID:38610086)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnaaf4	ENSDARG00000099161
mus_musculus	Dnaaf4	ENSMUSG00000092192
rattus_norvegicus	Dnaaf4	ENSRNOG00000056654

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), STUB1 (ENSG00000103266), SPAG1 (ENSG00000104450), SGTA (ENSG00000104969), TTC1 (ENSG00000113312), TTC31 (ENSG00000115282), UNC45A (ENSG00000140553), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), TOMM70 (ENSG00000154174), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725)

Protein

Protein identifiers

Dynein axonemal assembly factor 4 — Q8WXU2 (reviewed: Q8WXU2)

Alternative names: Dyslexia susceptibility 1 candidate gene 1 protein

All UniProt accessions (4): A0A0S2Z5Z4, B4DY92, E5RJ13, Q8WXU2

UniProt curated annotations — full annotation on UniProt →

Function. Axonemal dynein assembly factor required for ciliary motility. Involved in neuronal migration during development of the cerebral neocortex. May regulate the stability and proteasomal degradation of the estrogen receptors that play an important role in neuronal differentiation, survival and plasticity.

Subunit / interactions. Interacts with ZMYND10. Interacts with ESR1 and ESR2. Interacts with STUB1. Interacts with DNAAF2. Interacts with CCT3, CCT4, CCT5 and CCT8. Interacts with DNAAF6/PIH1D3.

Subcellular location. Nucleus. Cytoplasm. Dynein axonemal particle. Cell projection. Neuron projection.

Tissue specificity. Expressed in several tissues, including brain, lung, kidney and testis. In brain localizes to a fraction of cortical neurons and white matter glial cells.

Disease relevance. Dyslexia 1 (DYX1) [MIM:127700] A relatively common, complex cognitive disorder characterized by an impairment of reading performance despite adequate motivational, educational and intellectual opportunities. It is a multifactorial trait, with evidence for familial clustering and heritability. Disease susceptibility is associated with variants affecting the gene represented in this entry. A chromosomal aberration involving DNAAF4 has been found in a family affected by dyslexia. Translocation t(2;15)(q11;q21). Ciliary dyskinesia, primary, 25 (CILD25) [MIM:615482] A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WXU2-1	1	yes
Q8WXU2-2	2
Q8WXU2-3	3

RefSeq proteins (3): NP_001028731, NP_001028732, NP_570722* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007052	CS_dom	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR037894	CS_DYX1C1	Domain
IPR052004	Dynein_assembly_factor_4	Family

Pfam: PF04969

UniProt features (15 total): sequence variant 6, repeat 3, splice variant 3, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXU2-F1	84.00	0.53

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 248 (showing top): GOBP_COGNITION, GOBP_BEHAVIOR, MODULE_255, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_INNER_DYNEIN_ARM_ASSEMBLY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_AXONEMAL_DYNEIN_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (12): neuron migration (GO:0001764), cilium movement (GO:0003341), epithelial cilium movement involved in extracellular fluid movement (GO:0003351), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), learning or memory (GO:0007611), regulation of intracellular estrogen receptor signaling pathway (GO:0033146), outer dynein arm assembly (GO:0036158), inner dynein arm assembly (GO:0036159), establishment of localization in cell (GO:0051649), regulation of proteasomal protein catabolic process (GO:0061136), nervous system development (GO:0007399)

GO Molecular Function (2): nuclear estrogen receptor binding (GO:0030331), protein binding (GO:0005515)

GO Cellular Component (11): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), neuron projection (GO:0043005), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm head-tail coupling apparatus (GO:0120212), dynein axonemal particle (GO:0120293), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
axonemal dynein complex assembly	2
cytoplasm	2
sperm flagellum	2
cell migration	1
generation of neurons	1
microtubule-based movement	1
cilium movement	1
extracellular transport	1
microtubule-based transport	1
determination of bilateral symmetry	1
left/right pattern formation	1
animal organ development	1
circulatory system development	1
behavior	1
cognition	1
estrogen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
establishment of localization	1
cellular localization	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
system development	1
nuclear receptor binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
plasma membrane bounded cell projection	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAAF4	DCDC2	Q9UHG0	978
DNAAF4	KIAA0319	Q5VV43	972
DNAAF4	DNAAF6	Q9NQM4	957
DNAAF4	DNAAF3	Q8N9W5	898
DNAAF4	DNAAF1	Q8NEP3	860
DNAAF4	DNAAF2	Q9NVR5	857
DNAAF4	ROBO1	Q9Y6N7	844
DNAAF4	DNAAF11	Q86X45	811
DNAAF4	CFAP298	P57076	809
DNAAF4	DNAAF5	Q86Y56	800
DNAAF4	ZMYND10	O75800	799
DNAAF4	GCFC2	P16383	773
DNAAF4	DNAAF19	Q8IW40	768
DNAAF4	ATP2C2	O75185	748
DNAAF4	DNAI2	Q9GZS0	736

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
GABARAP	IPO5	psi-mi:“MI:0914”(association)	0.590
SPDL1	DNAAF4	psi-mi:“MI:0915”(physical association)	0.560
DNAAF4	SPDL1	psi-mi:“MI:0915”(physical association)	0.560
GABARAPL2	DNAAF4	psi-mi:“MI:0407”(direct interaction)	0.540
MAP1LC3C	DNAAF4	psi-mi:“MI:0407”(direct interaction)	0.540
DNAAF4	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.540
DNAAF4	MAP1LC3C	psi-mi:“MI:0915”(physical association)	0.540
GABARAP	DNAAF4	psi-mi:“MI:0407”(direct interaction)	0.520
GABARAPL1	DNAAF4	psi-mi:“MI:0407”(direct interaction)	0.520
DNAAF4	CALM1	psi-mi:“MI:0914”(association)	0.510
MAP1LC3B	DNAAF4	psi-mi:“MI:0407”(direct interaction)	0.440
DNAAF4	NCK2	psi-mi:“MI:0915”(physical association)	0.400
	DNAAF4	psi-mi:“MI:0915”(physical association)	0.370
KDM1A	DNAAF4	psi-mi:“MI:0915”(physical association)	0.370
GABARAP		psi-mi:“MI:0914”(association)	0.350
GCH1	ARHGAP42	psi-mi:“MI:0914”(association)	0.350
DNAAF4	RAP1BL	psi-mi:“MI:0914”(association)	0.350
CALM1	DNAAF4	psi-mi:“MI:0915”(physical association)	0.000
DNAAF2	DNAAF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): DYX1C1 (Two-hybrid), NCK2 (Affinity Capture-MS), DYX1C1 (Affinity Capture-Western), DYX1C1 (Affinity Capture-Western), DYX1C1 (Affinity Capture-MS), NCK2 (Affinity Capture-MS), DYX1C1 (Affinity Capture-MS), DYX1C1 (Affinity Capture-MS), STUB1 (Two-hybrid), SPDL1 (Two-hybrid), TRIM23 (Two-hybrid), KRT13 (Two-hybrid), EXOC5 (Two-hybrid), CRACR2B (Two-hybrid), DYX1C1 (Two-hybrid)

ESM2 similar proteins: A0A1L8G016, A1A5Q0, B3DH20, D3Z8X7, D4A1F2, E1BTG2, F1MF74, F1RA39, O14730, O60308, O88978, O94851, O95801, P51432, P70566, Q1RMR5, Q1RMT7, Q28FY0, Q2YDM7, Q3UHZ5, Q3UM18, Q4KLT3, Q4R3F0, Q4R8L2, Q5BJT6, Q5EA11, Q5ZJD3, Q6AZN0, Q6P5Q4, Q7Z569, Q80V31, Q863A4, Q863A5, Q863A6, Q863A7, Q86X45, Q8BML1, Q8CCP0, Q8R368, Q8R3H9

Diamond homologs: A4K2V0, A6HD62, A6ZRW3, D7REX8, F1RBN2, F4IRM4, F4JTI1, F4K487, F4KCL7, O13754, O14217, O16259, O35814, O48802, O54981, O94826, O95801, P07213, P23231, P25638, P31948, P33313, P38825, P53041, P53042, Q07617, Q12118, Q13451, Q15785, Q32PZ3, Q3KRD5, Q3ZBR5, Q43207, Q4R8N7, Q5EA11, Q5PPS5, Q5R8D8, Q5RAP0, Q5U2X2, Q5VJS5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Macroautophagy	5	41.2×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	125.4×	2e-08
mitophagy	5	113.6×	2e-08
autophagosome assembly	5	80.2×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	9
Uncertain significance	126
Likely benign	93
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069012	NC_000015.9:g.(?55731650)(55731799_?)del	Pathogenic
1071102	NM_130810.4(DNAAF4):c.1042_1043insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNACTGCAACCTCTGCCTCCCAGGTTGAAGCGATTTTCCTGCCTCAGCCTCAGCCTCCTGAGTAGCTGGGCTGAAGATTCTT (p.Ser348delinsPhePhePhePhePhePhePheXaaXaaXaaXaaCysAsnLeuCysLeuProGlyTer)	Pathogenic
1342101	NM_130810.4(DNAAF4):c.1153+1G>A	Pathogenic
2106741	NM_130810.4(DNAAF4):c.406-1G>C	Pathogenic
2427198	NC_000015.9:g.(?55789890)(55790527_?)del	Pathogenic
2427199	NC_000015.9:g.(?55783301)(55790527_?)del	Pathogenic
2427200	NC_000015.9:g.(?55722868)(55724820_?)del	Pathogenic
2500780	NM_130810.4(DNAAF4):c.784_893del (p.Trp262fs)	Pathogenic
254083	NM_130810.3(DNAAF4):c.784-?_893+?del	Pathogenic
2733790	NM_130810.4(DNAAF4):c.496dup (p.Gln166fs)	Pathogenic
2763909	NM_130810.4(DNAAF4):c.406-1G>A	Pathogenic
2809092	NM_130810.4(DNAAF4):c.191_195del (p.Ala64fs)	Pathogenic
2817773	NM_130810.4(DNAAF4):c.547C>T (p.Gln183Ter)	Pathogenic
2886575	NM_130810.4(DNAAF4):c.430dup (p.Ile144fs)	Pathogenic
2916383	NM_130810.4(DNAAF4):c.586_590del (p.Ile195_Lys196insTer)	Pathogenic
3016601	NM_130810.4(DNAAF4):c.563_567del (p.Ile188fs)	Pathogenic
3243905	NC_000015.9:g.(?55742400)(55742585_?)del	Pathogenic
3384971	NC_000015.9:g.(55727257_55731669)_(55731780_55742419)del	Pathogenic
3718369	NM_130810.4(DNAAF4):c.862_866del (p.Lys288fs)	Pathogenic
4076091	GRCh37/hg19 15q21.3(chr15:55702482-55775014)x1	Pathogenic
410963	NM_130810.4(DNAAF4):c.165_167delinsCT (p.Pro56fs)	Pathogenic
417541	NC_000015.10:g.(?55450222)(55450367_?)del	Pathogenic
525588	NC_000015.10:g.(?55430650)(55432622_?)del	Pathogenic
577768	NM_130810.4(DNAAF4):c.583del (p.Lys194_Ile195insTer)	Pathogenic
643553	NM_130810.4(DNAAF4):c.934del (p.Ala312fs)	Pathogenic
646956	NC_000015.10:g.(?55430664)(55432608_?)del	Pathogenic
68449	NM_130810.4(DNAAF4):c.325G>T (p.Glu109Ter)	Pathogenic
832519	NC_000015.10:g.(?55418015)(55508896_?)del	Pathogenic
860083	NM_130810.4(DNAAF4):c.354del (p.Ala119fs)	Pathogenic
869382	NM_130810.4(DNAAF4):c.589_593del (p.Tyr197fs)	Pathogenic

SpliceAI

2131 predictions. Top by Δscore:

Variant	Effect	Δscore
15:55434899:CCATA:C	donor_loss	1.0000
15:55434900:CATA:C	donor_loss	1.0000
15:55434901:ATAC:A	donor_loss	1.0000
15:55434902:TACCT:T	donor_loss	1.0000
15:55434903:ACCT:A	donor_loss	1.0000
15:55434904:CCTTA:C	donor_loss	1.0000
15:55439470:A:AC	donor_gain	1.0000
15:55439470:ACTTT:A	donor_gain	1.0000
15:55439471:C:CG	donor_gain	1.0000
15:55439471:CTTT:C	donor_gain	1.0000
15:55439471:CTTTC:C	donor_gain	1.0000
15:55439474:T:A	donor_gain	1.0000
15:55450223:T:TA	donor_gain	1.0000
15:55454875:A:AC	donor_gain	1.0000
15:55454876:C:CC	donor_gain	1.0000
15:55491117:ACTTA:A	donor_loss	1.0000
15:55491118:CTTA:C	donor_loss	1.0000
15:55491119:TTA:T	donor_loss	1.0000
15:55491120:TA:T	donor_loss	1.0000
15:55491121:ACC:A	donor_loss	1.0000
15:55491122:C:CT	donor_loss	1.0000
15:55491254:CAA:C	acceptor_gain	1.0000
15:55491257:C:CC	acceptor_gain	1.0000
15:55497710:ACCAC:A	donor_gain	1.0000
15:55497711:CCA:C	donor_gain	1.0000
15:55497711:CCACC:C	donor_gain	1.0000
15:55498201:TCTTA:T	donor_loss	1.0000
15:55498202:CTTA:C	donor_loss	1.0000
15:55498203:TTAC:T	donor_loss	1.0000
15:55498204:TACCT:T	donor_loss	1.0000

AlphaMissense

2790 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:55432535:C:G	R372P	0.996
15:55432497:C:G	G385R	0.995
15:55432532:C:T	G373E	0.994
15:55434963:C:G	R330P	0.994
15:55434961:C:G	A331P	0.993
15:55432526:G:T	A375E	0.992
15:55432536:G:T	R372S	0.992
15:55432527:C:G	A375P	0.991
15:55432533:C:G	G373R	0.991
15:55432533:C:T	G373R	0.991
15:55432538:C:G	R371P	0.991
15:55434948:A:G	L335P	0.991
15:55434916:C:G	D346H	0.989
15:55430759:C:G	A392P	0.988
15:55434955:A:G	C333R	0.988
15:55498211:A:G	L40P	0.988
15:55430776:A:G	L386P	0.987
15:55430779:C:T	G385D	0.987
15:55430758:G:T	A392E	0.985
15:55434953:G:C	C333W	0.985
15:55435026:G:T	A309D	0.985
15:55435027:C:G	A309P	0.985
15:55432514:A:G	L379P	0.984
15:55497736:A:G	W83R	0.984
15:55497736:A:T	W83R	0.984
15:55439476:C:G	G297R	0.983
15:55439476:C:T	G297R	0.983
15:55432532:C:A	G373V	0.980
15:55432547:G:T	A368E	0.980
15:55450251:G:T	R252S	0.980

dbSNP variants (sampled 300 via entrez): RS1000010843 (15:55507860 A>G), RS1000023854 (15:55428667 T>A), RS1000130313 (15:55435143 G>A,T), RS1000134626 (15:55473801 G>A), RS1000139238 (15:55462592 C>G), RS1000153002 (15:55429170 C>T), RS1000160859 (15:55486457 G>A,C), RS1000194247 (15:55420547 T>A), RS1000218048 (15:55502772 C>T), RS1000230057 (15:55449923 T>C,G), RS1000292139 (15:55468621 T>C), RS1000296108 (15:55486675 T>A,C), RS1000305947 (15:55428853 G>C), RS1000336805 (15:55461497 T>C), RS1000339952 (15:55478610 A>G)

Disease associations

OMIM: gene MIM:608706 | disease phenotypes: MIM:127700, MIM:615482, MIM:607624, MIM:244400

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ciliary dyskinesia 25	Definitive	Autosomal recessive
primary ciliary dyskinesia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
primary ciliary dyskinesia 25	Definitive	AR

Mondo (4): dyslexia, susceptibility to, 1 (MONDO:0007487), primary ciliary dyskinesia 25 (MONDO:0014203), Griscelli syndrome type 2 (MONDO:0011872), primary ciliary dyskinesia (MONDO:0016575)

Orphanet (3): Primary ciliary dyskinesia (Orphanet:244), Griscelli syndrome (Orphanet:381), Griscelli syndrome type 2 (Orphanet:79477)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000119	Abnormality of the genitourinary system
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000750	Delayed speech and language development
HP:0000789	Infertility
HP:0000924	Abnormality of the skeletal system
HP:0001217	Clubbing
HP:0001627	Abnormal heart morphology
HP:0001651	Dextrocardia
HP:0001669	Transposition of the great arteries
HP:0001696	Situs inversus totalis
HP:0001719	Double outlet right ventricle
HP:0001742	Nasal congestion
HP:0001746	Asplenia
HP:0001748	Polysplenia
HP:0002011	Morphological central nervous system abnormality
HP:0002020	Gastroesophageal reflux
HP:0002110	Bronchiectasis
HP:0002119	Ventriculomegaly
HP:0002167	Abnormal speech pattern
HP:0002205	Recurrent respiratory infections
HP:0002257	Chronic rhinitis
HP:0002566	Intestinal malrotation

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
C537302	Griscelli syndrome type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Air Pollutants	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	increases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	increases methylation	1
sodium arsenite	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Estradiol	affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Smoke	increases abundance, increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide
NCT00783887	Not specified	COMPLETED	Diagnosis of Primary Ciliary Dyskinesia
NCT00807482	Not specified	RECRUITING	Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
NCT01070914	Not specified	UNKNOWN	Early Detection and Characterization of Primary Ciliary Dyskinesia
NCT01155115	Not specified	COMPLETED	Inflammatory and Microbiologic Markers in Sputum: Comparing Cystic Fibrosis With Primary Ciliary Dyskinesia
NCT01246258	Not specified	COMPLETED	Otolith Function in Patients With Primary Ciliary Dyskinesia
NCT01929356	Not specified	RECRUITING	Chest Physiotherapy and Lung Function in Primary Ciliary Dyskinesia
NCT02389049	Not specified	COMPLETED	Genetics of Primary Ciliary Dyskinesia
NCT02419365	Not specified	RECRUITING	International Primary Ciliary Dyskinesia (PCD) Registry
NCT02699177	Not specified	UNKNOWN	In Vivo Measurements of Nasal Ciliary Beat Frequency by Using Interferometry
NCT02704455	Not specified	NOT_YET_RECRUITING	Registry Study on Primary Ciliary Dyskinesia in Chinese Children
NCT03271840	Not specified	COMPLETED	Registry for Primary Ciliary Dyskinesia
NCT03279965	Not specified	UNKNOWN	MRI in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03320382	Not specified	UNKNOWN	Multiple Breath Washout, a Clinimetric Dataset
NCT03370029	Not specified	COMPLETED	Respiratory Muscle Strength, Exercise Capacity and Physical Activity Levels in Children Primary Ciliary Dyskinesia
NCT03494894	Not specified	COMPLETED	Bacteriological Link Between Upper and Lower Airways in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03517865	Not specified	ACTIVE_NOT_RECRUITING	International Primary Ciliary Dyskinesia Cohort
NCT03606200	Not specified	RECRUITING	Swiss Primary Ciliary Dyskinesia Registry
NCT03704207	Not specified	RECRUITING	Utility of PCD Diagnostics to Improve Clinical Care
NCT03704896	Not specified	UNKNOWN	PRospective Observational Multicentre Study on VAriability of Lung Function in Stable PCD Patients
NCT03801395	Not specified	COMPLETED	PCD New Gene Discovery
NCT03809091	Not specified	UNKNOWN	WGS of Korean Idiopathic Bronchiectasis
NCT03832491	Not specified	COMPLETED	Effect of Game Based Approach on Oxygenation, Functional Capacity and Quality of Life in Primary Ciliary Dyskinesia
NCT04161313	Not specified	COMPLETED	Respiratory Function, Exercise Capacity and Peripheral Muscle Strength Among Patients With CF, PCD and Healthy Children
NCT04476433	Not specified	COMPLETED	Intervention in Chronic Pediatric Patients and Their Families.
NCT04489472	Not specified	UNKNOWN	The Effect of a Dietary Supplement Rich in Nitric Oxide in Patients Diagnosed With Primary Ciliary Dyskinesia.
NCT04602481	Not specified	RECRUITING	Living With Primary Ciliary Dyskinesia (Living With PCD)