DRC4

Summary

DRC4 (dynein regulatory complex subunit 4, HGNC:4166) is a protein-coding gene on chromosome 16q24.3, encoding Dynein regulatory complex subunit 4 (O95995). Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.

This gene includes 11 exons spanning 25 kb and maps to a region of chromosome 16 that is sometimes deleted in breast and prostrate cancer. The second intron contains an apparently intronless gene, C16orf3, that is transcribed in the opposite orientation. This gene is a putative tumor suppressor gene. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ciliary dyskinesia 33 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 477 total — 17 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 53
• MANE Select transcript: NM_001481

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4166
Approved symbol	DRC4
Name	dynein regulatory complex subunit 4
Location	16q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141013
Ensembl biotype	protein_coding
OMIM	605178
Entrez	2622

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 10 protein_coding, 7 retained_intron, 6 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000268699, ENST00000536122, ENST00000537797, ENST00000540721, ENST00000561675, ENST00000563980, ENST00000564392, ENST00000564789, ENST00000564802, ENST00000564853, ENST00000565000, ENST00000565062, ENST00000565957, ENST00000566266, ENST00000568284, ENST00000568664, ENST00000568705, ENST00000569399, ENST00000569558, ENST00000620723, ENST00000889286, ENST00000889287, ENST00000964021, ENST00000964022, ENST00000964023

RefSeq mRNA: 4 — MANE Select: NM_001481 NM_001286205, NM_001286208, NM_001286209, NM_001481

CCDS: CCDS10992, CCDS67101, CCDS73932

Canonical transcript exons

ENST00000268699 — 11 exons

Exon	Start	End
ENSE00001174396	90022680	90022724
ENSE00003606096	90027636	90027722
ENSE00003802251	90031299	90031496
ENSE00003804978	90035633	90035687
ENSE00003805713	90037762	90037848
ENSE00003806469	90042470	90042535
ENSE00003808046	90040300	90040509
ENSE00003809165	90037232	90037399
ENSE00003809750	90032718	90032924
ENSE00003810536	90036381	90036586
ENSE00003842300	90043196	90044960

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 97.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7553 / max 59.4145, expressed in 1658 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155689	4.7137	1572
155687	1.9411	872
155688	0.1005	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.07	gold quality
sural nerve	UBERON:0015488	94.12	gold quality
type B pancreatic cell	CL:0000169	93.54	gold quality
olfactory bulb	UBERON:0002264	93.38	gold quality
adenohypophysis	UBERON:0002196	93.33	gold quality
pituitary gland	UBERON:0000007	92.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.57	gold quality
metanephros cortex	UBERON:0010533	91.78	gold quality
right lobe of thyroid gland	UBERON:0001119	91.76	gold quality
left lobe of thyroid gland	UBERON:0001120	91.51	gold quality
thyroid gland	UBERON:0002046	91.11	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.92	gold quality
left testis	UBERON:0004533	90.23	gold quality
cerebellar hemisphere	UBERON:0002245	90.15	gold quality
right frontal lobe	UBERON:0002810	90.07	gold quality
cerebellar cortex	UBERON:0002129	90.02	gold quality
left ovary	UBERON:0002119	89.97	gold quality
apex of heart	UBERON:0002098	89.90	gold quality
lower esophagus mucosa	UBERON:0035834	89.64	gold quality
body of pancreas	UBERON:0001150	89.46	gold quality
right testis	UBERON:0004534	89.46	gold quality
heart left ventricle	UBERON:0002084	88.94	gold quality
cerebellum	UBERON:0002037	88.90	gold quality
right adrenal gland	UBERON:0001233	88.74	gold quality
right ovary	UBERON:0002118	88.66	gold quality
testis	UBERON:0000473	88.52	gold quality
cardiac ventricle	UBERON:0002082	88.50	gold quality
endometrium epithelium	UBERON:0004811	88.38	gold quality
right adrenal gland cortex	UBERON:0035827	88.27	gold quality
diaphragm	UBERON:0001103	88.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting DRC4, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-4796-3P	99.08	68.38	1681

Literature-anchored findings (GeneRIF, showing 9)

• A two-hybrid screen for proteins that interact with NS1 from influenza A yielded growth arrest-specific protein 8. Gas8 associated with NS1 in vitro and in vivo. (PMID:19995461)
• Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex. (PMID:26387594)
• Study identifies bi-allelic loss-of-function mutations in GAS8 as a cause for primary ciliary dyskinesia, and unveils the key importance of the protein encoded by this gene in N-DRC integrity and in the proper alignment of axonemal microtubules in humans. (PMID:27120127)
• Here, we generate the first mouse with a Gas8 mutation and show that it causes severe Primary Ciliary Dyskinesia (PCD)phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8 (PMID:27472056)
• In papillary thyroid carcinoma (PTC) cell lines, GAS8-AS1 inhibited proliferation, activated autophagy, and increased ATG5 expression. Downregulation of ATG5 reversed GAS8-AS1-mediated activation of autophagy leading to cell death, revealing a novel mechanism of the GAS8-AS1-ATG5 axis in PTC cell lines. (PMID:29327301)
• Expression of GAS8-AS1 or GAS8 is significantly decreased in hepatocellular carcinoma tissues and is associated with a poor prognosis among hepatocellular carcinoma patients. (PMID:30228180)
• The current study shows significance of GAS8 and GAS8-AS1 in the pathogenesis of MS and the putative role of GAS8-AS1 as a diagnostic biomarker in a subset of patients. (PMID:31003831)
• Expression analysis of growth arrest specific 8 and its anti-sense in breast cancer tissues. (PMID:32165089)
• LncRNA GAS8-AS1 downregulates lncRNA NEAT1 to inhibit glioblastoma cell proliferation. (PMID:33942556)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gas8	ENSDARG00000101431
mus_musculus	Gas8	ENSMUSG00000040220
rattus_norvegicus	Gas8	ENSRNOG00000026964
drosophila_melanogaster	Gas8	FBGN0029667

Protein

Protein identifiers

Dynein regulatory complex subunit 4 — O95995 (reviewed: O95995)

Alternative names: Growth arrest-specific protein 11, Growth arrest-specific protein 8

All UniProt accessions (7): O95995, A0A087WZT7, A0A384MR00, H3BME0, H3BP65, H3BQT7, H3BUA7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Plays an important role in the assembly of the N-DRC linker. Plays dual roles at both the primary (or non-motile) cilia to regulate hedgehog signaling and in motile cilia to coordinate cilia movement. Required for proper motile cilia functioning. Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity in a GRK2-dependent manner.

Subunit / interactions. Component of the nexin-dynein regulatory complex (N-DRC). Interacts with microtubules. Interacts with SMO. Interacts (via coiled-coil domains) with RAB3B (in GTP-bound form). Interacts with DRC1. Interacts with DRC7.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Cilium. Flagellum. Cilium axoneme. Cilium basal body. Golgi apparatus. Flagellum axoneme.

Tissue specificity. Expressed in respiratory epithelial cells (at protein level). Expressed in the heart, skeletal muscle, pancreas, liver, brain, trachea and lung. Weakly or not expressed in placenta and kidney.

Disease relevance. Ciliary dyskinesia, primary, 33 (CILD33) [MIM:616726] A form of primary ciliary dyskinesia, 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. CILD33 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DRC4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95995-1	1	yes
O95995-2	2

RefSeq proteins (4): NP_001273134, NP_001273137, NP_001273138, NP_001472* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025593	GAS8_dom	Domain
IPR039308	GAS8	Family

Pfam: PF13851

UniProt features (15 total): sequence variant 5, region of interest 4, sequence conflict 2, chain 1, coiled-coil region 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95995-F1	85.12	0.60

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5635838	Activation of SMO

MSigDB gene sets: 265 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOMF_GTPASE_BINDING, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_SPECIFICATION_OF_SYMMETRY, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, MODULE_379, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOBP_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY, GOBP_HEAD_DEVELOPMENT

GO Biological Process (16): microtubule cytoskeleton organization (GO:0000226), epithelial cilium movement involved in extracellular fluid movement (GO:0003351), determination of left/right symmetry (GO:0007368), brain development (GO:0007420), negative regulation of cell population proliferation (GO:0008285), flagellated sperm motility (GO:0030317), axoneme assembly (GO:0035082), cilium organization (GO:0044782), positive regulation of smoothened signaling pathway (GO:0045880), establishment of localization in cell (GO:0051649), cilium movement involved in cell motility (GO:0060294), protein localization to cilium (GO:0061512), protein-containing complex assembly (GO:0065003), positive regulation of protein localization to cilium (GO:1903566), intracellular protein localization (GO:0008104), cell motility (GO:0048870)

GO Molecular Function (3): microtubule binding (GO:0008017), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (18): extracellular region (GO:0005576), Golgi apparatus (GO:0005794), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), motile cilium (GO:0031514), ciliary basal body (GO:0036064), sperm flagellum (GO:0036126), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), microtubule cytoskeleton (GO:0015630), cell projection (GO:0042995), 9+2 motile cilium (GO:0097729)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hedgehog ‘on’ state	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
sperm flagellum	3
cilium movement	2
cilium-dependent cell motility	2
cellular component assembly	2
cytoplasm	2
cytoskeleton	2
cilium	2
cytoskeleton organization	1
microtubule-based process	1
extracellular transport	1
microtubule-based transport	1
determination of bilateral symmetry	1
left/right pattern formation	1
central nervous system development	1
animal organ development	1
head development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cilium movement involved in cell motility	1
sperm motility	1
microtubule bundle formation	1
cilium assembly	1
organelle organization	1
plasma membrane bounded cell projection organization	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
establishment of localization	1
cellular localization	1
cell motility	1
protein localization to organelle	1
protein-containing complex organization	1
protein localization to cilium	1
regulation of protein localization to cilium	1
positive regulation of protein localization	1
macromolecule localization	1
cellular process	1
tubulin binding	1

Protein interactions and networks

STRING

1069 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DRC4	DRC2	Q8IXS2	908
DRC4	DRC1	Q96MC2	855
DRC4	SERPINE2	P07093	811
DRC4	DRC7	Q8IY82	803
DRC4	DRC5	Q5JU00	783
DRC4	RSPH4A	Q5TD94	748
DRC4	DNAI2	Q9GZS0	744
DRC4	DRC3	Q9H069	735
DRC4	DNALI1	O14645	734
DRC4	RSPH1	Q8WYR4	733
DRC4	CCDC39	Q9UFE4	726
DRC4	CCDC40	Q4G0X9	703
DRC4	RSPH9	Q9H1X1	687
DRC4	ODAD2	Q5T2S8	624
DRC4	DNAH5	Q8TE73	620

IntAct

341 interactions, top by confidence:

A	B	Type	Score
GAS8	POTEB3	psi-mi:“MI:0915”(physical association)	0.560
GAS8	ZNF620	psi-mi:“MI:0915”(physical association)	0.560
GAS8	LZTS1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	GRIPAP1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	LMO1	psi-mi:“MI:0915”(physical association)	0.560
GSTA4	GAS8	psi-mi:“MI:0915”(physical association)	0.560
GAS8	HOMER3	psi-mi:“MI:0915”(physical association)	0.560
GAS8	LMO2	psi-mi:“MI:0915”(physical association)	0.560
TRAF5	GAS8	psi-mi:“MI:0915”(physical association)	0.560
PLK4	GAS8	psi-mi:“MI:0915”(physical association)	0.560
GAS8	MRFAP1L1	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	GAS8	psi-mi:“MI:0915”(physical association)	0.560
GAS8	RINT1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	GPRASP3	psi-mi:“MI:0915”(physical association)	0.560
GAS8	EAF1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	SKIL	psi-mi:“MI:0915”(physical association)	0.560
GAS8	CDR2	psi-mi:“MI:0915”(physical association)	0.560
KRT15	GAS8	psi-mi:“MI:0915”(physical association)	0.560
GAS8	TSFM	psi-mi:“MI:0915”(physical association)	0.560
GAS8	ZNF792	psi-mi:“MI:0915”(physical association)	0.560
GAS8	FHL2	psi-mi:“MI:0915”(physical association)	0.560
GAS8	TRIM54	psi-mi:“MI:0915”(physical association)	0.560
GAS8	RALBP1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	GCC1	psi-mi:“MI:0915”(physical association)	0.560
GAS8	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
GAS8	RBAK	psi-mi:“MI:0915”(physical association)	0.560
ZBTB39	GAS8	psi-mi:“MI:0915”(physical association)	0.560
GAS8	KRT16	psi-mi:“MI:0915”(physical association)	0.560
GAS8	CIAO1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (122): GAS8 (Co-fractionation), GAS8 (Co-fractionation), CIAO1 (Affinity Capture-MS), GAS8 (Synthetic Lethality), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid), GAS8 (Two-hybrid)

ESM2 similar proteins: A0PJP4, A2VDP1, A5D7M3, B2RW38, D3ZUQ0, F1QNW4, O00291, O14645, O43805, O75146, O75150, O95995, Q17QG3, Q26630, Q3U319, Q499U4, Q4FZV3, Q4R3K5, Q4R7K7, Q4R7Y8, Q4V328, Q5DTM8, Q5E9C3, Q5EBL4, Q5RAU7, Q5T655, Q5VTR2, Q5ZLS3, Q60779, Q68CZ1, Q6DGZ3, Q6GN86, Q7XJ96, Q7Z3E2, Q8BKE9, Q8BR07, Q8BVN8, Q8C9S4, Q8CG73, Q8CJB9

Diamond homologs: A5D7M3, F1QNW4, O15697, O95995, Q499U4, Q60779, Q7XJ96, Q8MT08

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GAS8	“form complex”	“Nexin-dynein regulatory complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	8
Uncertain significance	181
Likely benign	184
Benign	65

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1076474	NM_001481.3(DRC4):c.886C>T (p.Gln296Ter)	Pathogenic
1455472	NC_000016.9:g.(?90089130)(90094150_?)del	Pathogenic
219122	NM_001481.3(GAS8):c.927C>A (p.Cys309Ter)	Pathogenic
219123	NM_001481.3(DRC4):c.1000C>T (p.Arg334Ter)	Pathogenic
219124	NM_001481.3(DRC4):c.1069C>T (p.Gln357Ter)	Pathogenic
2201812	NM_001481.3(DRC4):c.887del (p.Gln296fs)	Pathogenic
2424183	NC_000016.9:g.(?90089130)(90089152_?)del	Pathogenic
2663811	NM_001481.3(DRC4):c.189G>A (p.Trp63Ter)	Pathogenic
2898953	NM_001481.3(DRC4):c.97G>T (p.Glu33Ter)	Pathogenic
3243533	NC_000016.9:g.(?90089130)(90109753_?)del	Pathogenic
3610990	NM_001481.3(DRC4):c.796G>T (p.Glu266Ter)	Pathogenic
3639758	NM_001481.3(DRC4):c.1105_1106insTA (p.Arg369fs)	Pathogenic
3679698	NM_001481.3(DRC4):c.278_279dup (p.Glu94fs)	Pathogenic
475553	NC_000016.10:g.(?90022702)(90040529_?)del	Pathogenic
4783817	NM_001481.3(DRC4):c.547C>T (p.Arg183Ter)	Pathogenic
4792002	NM_001481.3(DRC4):c.145C>T (p.Arg49Ter)	Pathogenic
955888	NM_001481.3(DRC4):c.718dup (p.Ile240fs)	Pathogenic
1065987	NM_001481.3(DRC4):c.1011+2T>C	Likely pathogenic
2431345	NM_001481.3(DRC4):c.495+1G>T	Likely pathogenic
3001041	NM_001481.3(DRC4):c.757-1G>C	Likely pathogenic
3719545	NM_001481.3(DRC4):c.1221+1G>T	Likely pathogenic
4502245	NM_001481.3(DRC4):c.495+1G>A	Likely pathogenic
4782919	NM_001481.3(DRC4):c.1011+1G>T	Likely pathogenic
4791533	NM_001481.3(DRC4):c.924+2_924+3del	Likely pathogenic
804479	NM_001481.3(GAS8):c.865del (p.Glu289fs)	Likely pathogenic

SpliceAI

1925 predictions. Top by Δscore:

Variant	Effect	Δscore
16:90022726:T:A	donor_loss	1.0000
16:90031495:AGGT:A	donor_loss	1.0000
16:90031497:G:A	donor_loss	1.0000
16:90031497:G:GG	donor_gain	1.0000
16:90036583:CAAG:C	donor_loss	1.0000
16:90036585:AG:A	donor_loss	1.0000
16:90036586:GG:G	donor_loss	1.0000
16:90036588:T:A	donor_loss	1.0000
16:90037395:TGCTT:T	donor_gain	1.0000
16:90037396:GCTT:G	donor_gain	1.0000
16:90037396:GCTTG:G	donor_gain	1.0000
16:90037397:CTT:C	donor_gain	1.0000
16:90037398:TT:T	donor_gain	1.0000
16:90037398:TTG:T	donor_loss	1.0000
16:90037400:G:GG	donor_gain	1.0000
16:90037400:GTG:G	donor_loss	1.0000
16:90037401:TGAG:T	donor_loss	1.0000
16:90037760:A:AG	acceptor_gain	1.0000
16:90037761:G:GG	acceptor_gain	1.0000
16:90037761:GT:G	acceptor_gain	1.0000
16:90037761:GTGC:G	acceptor_gain	1.0000
16:90040432:G:GT	donor_gain	1.0000
16:90040507:G:GT	donor_gain	1.0000
16:90040507:GAGGT:G	donor_loss	1.0000
16:90040508:AGGT:A	donor_loss	1.0000
16:90040509:GGTA:G	donor_loss	1.0000
16:90040511:T:G	donor_loss	1.0000
16:90042464:CCTCA:C	acceptor_loss	1.0000
16:90042465:CTCAG:C	acceptor_loss	1.0000
16:90042466:TCAGG:T	acceptor_loss	1.0000

AlphaMissense

3172 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:90031354:G:C	R49P	0.996
16:90031375:G:C	R56P	0.995
16:90032743:T:C	L105P	0.995
16:90031345:G:C	R46P	0.989
16:90036582:T:C	L251P	0.987
16:90031453:G:C	R82P	0.985
16:90036570:T:C	L247P	0.985
16:90031369:T:C	L54P	0.983
16:90036532:G:C	K234N	0.983
16:90036532:G:T	K234N	0.983
16:90031333:T:C	L42P	0.982
16:90036562:C:A	N244K	0.982
16:90036562:C:G	N244K	0.982
16:90036564:T:C	L245P	0.981
16:90031417:T:C	L70P	0.978
16:90031467:G:C	A87P	0.977
16:90031441:G:C	R78P	0.975
16:90031339:G:C	R44P	0.974
16:90031438:T:C	L77P	0.974
16:90036495:T:C	L222P	0.973
16:90031377:G:C	D57H	0.972
16:90032728:A:C	Q100P	0.972
16:90031431:G:C	A75P	0.971
16:90036515:G:C	A229P	0.971
16:90036507:A:C	H226P	0.970
16:90031362:T:C	F52L	0.969
16:90031364:C:A	F52L	0.969
16:90031364:C:G	F52L	0.969
16:90031392:T:C	F62L	0.969
16:90031394:C:A	F62L	0.969

dbSNP variants (sampled 300 via entrez): RS1000012609 (16:90034024 A>G), RS1000154992 (16:90040868 G>A), RS1000195485 (16:90038393 A>G), RS1000216103 (16:90030855 G>C), RS1000530066 (16:90027052 A>G), RS1000534048 (16:90031945 G>C), RS1000587765 (16:90031663 G>A,C), RS1000939507 (16:90022265 G>C), RS1001009276 (16:90024992 T>C), RS1001057600 (16:90019950 GGGGAT>G), RS1001141217 (16:90019668 C>T), RS1001217069 (16:90029820 G>A), RS1001442844 (16:90025099 C>G), RS1001490169 (16:90029923 A>G,T), RS1001549964 (16:90027430 G>A,C)

Disease associations

OMIM: gene MIM:605178 | disease phenotypes: MIM:616726, MIM:209850, MIM:244400

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ciliary dyskinesia 33	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 33	Definitive	AR

Mondo (3): primary ciliary dyskinesia 33 (MONDO:0014750), autism (MONDO:0005260), primary ciliary dyskinesia (MONDO:0016575)

Orphanet (1): Primary ciliary dyskinesia (Orphanet:244)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000119	Abnormality of the genitourinary system
HP:0000238	Hydrocephalus
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:0000924	Abnormality of the skeletal system
HP:0001217	Clubbing
HP:0001627	Abnormal heart morphology
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:0002110	Bronchiectasis
HP:0002119	Ventriculomegaly
HP:0002257	Chronic rhinitis
HP:0002566	Intestinal malrotation
HP:0002643	Neonatal respiratory distress
HP:0002783	Recurrent lower respiratory tract infections
HP:0002837	Recurrent bronchitis
HP:0002878	Respiratory failure
HP:0003251	Male infertility
HP:0005301	Persistent left superior vena cava
HP:0005425	Recurrent sinopulmonary infections

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_280	Brain morphology (MOSTest)	2.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases methylation	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
potassium perchlorate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases response to substance	1
Selenium	increases expression, affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Vanadates	decreases expression	1
Vitamin E	decreases expression, increases expression, affects cotreatment	1
Asbestos, Crocidolite	affects expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms