DNAH1

Summary

DNAH1 (dynein axonemal heavy chain 1, HGNC:2940) is a protein-coding gene on chromosome 3p21.1, encoding Dynein axonemal heavy chain 1 (Q9P2D7). Force generating protein of cilia required for sperm flagellum motility.

This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile.

Source: NCBI Gene 25981 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 18 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 2,966 total — 81 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 60
• MANE Select transcript: NM_015512

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2940
Approved symbol	DNAH1
Name	dynein axonemal heavy chain 1
Location	3p21.1
Locus type	gene with protein product
Status	Approved
Aliases	XLHSRF-1, DNAHC1, HDHC7, HL-11, HL11
Ensembl gene	ENSG00000114841
Ensembl biotype	protein_coding
OMIM	603332
Entrez	25981

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 retained_intron, 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000420323, ENST00000466628, ENST00000480649, ENST00000486752, ENST00000487254, ENST00000488988, ENST00000490713, ENST00000497875

RefSeq mRNA: 1 — MANE Select: NM_015512 NM_015512

CCDS: CCDS46842

Canonical transcript exons

ENST00000420323 — 78 exons

Exon	Start	End
ENSE00001331260	52316319	52316545
ENSE00001661849	52388418	52388609
ENSE00001785640	52388806	52388937
ENSE00003459739	52360311	52360424
ENSE00003469643	52384786	52384977
ENSE00003476006	52375955	52375993
ENSE00003482584	52395308	52395466
ENSE00003483019	52385337	52385447
ENSE00003483257	52353380	52353633
ENSE00003487168	52323808	52323880
ENSE00003487386	52364638	52364724
ENSE00003491456	52327882	52328014
ENSE00003492502	52399545	52399779
ENSE00003493826	52351962	52352103
ENSE00003498209	52349989	52350108
ENSE00003498816	52332142	52332394
ENSE00003500912	52393334	52393485
ENSE00003501026	52345495	52345706
ENSE00003501311	52396868	52397044
ENSE00003504043	52375240	52375413
ENSE00003506278	52352552	52352707
ENSE00003511491	52361661	52361766
ENSE00003512357	52366457	52366548
ENSE00003520604	52354843	52355055
ENSE00003524216	52331148	52331309
ENSE00003526157	52326735	52326891
ENSE00003531202	52386160	52386345
ENSE00003537812	52391179	52391328
ENSE00003540486	52356614	52356778
ENSE00003543008	52368741	52368918
ENSE00003544304	52379905	52380135
ENSE00003555235	52395547	52395678
ENSE00003556104	52388167	52388334
ENSE00003556491	52348888	52349081
ENSE00003560517	52322409	52322775
ENSE00003563832	52391443	52391603
ENSE00003574641	52358558	52358737
ENSE00003592630	52357614	52357735
ENSE00003595347	52386662	52386853
ENSE00003596217	52370477	52370635
ENSE00003596696	52326140	52326314
ENSE00003597050	52344490	52344647
ENSE00003597466	52372227	52372387
ENSE00003598328	52346472	52346770
ENSE00003598487	52383860	52384031
ENSE00003600257	52347824	52347974
ENSE00003601171	52369825	52370019
ENSE00003613285	52382320	52382455
ENSE00003614356	52364833	52365019
ENSE00003614994	52383386	52383594
ENSE00003620631	52350508	52350590
ENSE00003627800	52392830	52393025
ENSE00003634091	52372896	52373053
ENSE00003636074	52370110	52370229
ENSE00003643270	52359246	52359386
ENSE00003645117	52394465	52394661
ENSE00003646058	52370718	52370825
ENSE00003647054	52398850	52399201
ENSE00003650067	52398032	52398162
ENSE00003650368	52390935	52391054
ENSE00003654615	52357898	52358003
ENSE00003654852	52349195	52349420
ENSE00003655317	52396368	52396538
ENSE00003659185	52381640	52381836
ENSE00003662748	52362995	52363144
ENSE00003663766	52366733	52366887
ENSE00003664680	52389461	52389586
ENSE00003664853	52378602	52378780
ENSE00003665298	52394915	52395059
ENSE00003666807	52359916	52360079
ENSE00003666922	52371946	52372086
ENSE00003670758	52400325	52400492
ENSE00003672020	52362388	52362501
ENSE00003673063	52392464	52392689
ENSE00003677230	52353103	52353301
ENSE00003680817	52396618	52396797
ENSE00003681902	52361164	52361352
ENSE00003683293	52397707	52397877

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 96.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1502 / max 41.4998, expressed in 48 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36842	0.1212	44
36841	0.0290	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.08	gold quality
bronchial epithelial cell	CL:0002328	94.67	gold quality
bronchus	UBERON:0002185	93.41	gold quality
granulocyte	CL:0000094	91.20	gold quality
left testis	UBERON:0004533	87.35	gold quality
right testis	UBERON:0004534	87.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.41	gold quality
right lobe of liver	UBERON:0001114	85.25	gold quality
right frontal lobe	UBERON:0002810	84.42	gold quality
testis	UBERON:0000473	84.37	gold quality
bone marrow cell	CL:0002092	84.09	gold quality
tendon of biceps brachii	UBERON:0008188	83.91	silver quality
spleen	UBERON:0002106	83.49	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.99	gold quality
sperm	CL:0000019	82.88	gold quality
sural nerve	UBERON:0015488	82.37	gold quality
blood	UBERON:0000178	82.21	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.21	silver quality
right hemisphere of cerebellum	UBERON:0014890	81.59	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.40	gold quality
small intestine	UBERON:0002108	80.35	gold quality
oviduct epithelium	UBERON:0004804	80.15	gold quality
right lung	UBERON:0002167	80.12	gold quality
cerebellar hemisphere	UBERON:0002245	80.04	gold quality
cerebellar cortex	UBERON:0002129	79.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.64	gold quality
fallopian tube	UBERON:0003889	79.59	gold quality
left adrenal gland cortex	UBERON:0035825	79.58	gold quality
metanephros cortex	UBERON:0010533	79.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.75

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 16)

• Male carriers of the mutations always exhibit asthenozoospermia, whereas female carriers manifest no alterations in either fertility or pulmonary clearance. (PMID:18492703)
• Dynein motor function is important for regulating Gag and viral RNA egress on endosomal membranes in the cytoplasm to directly impact on viral production. (PMID:19286658)
• clathrin serving as a regulator of SNX4-dependent transport; upon clathrin release, dynein may bind SNX4 and mediate retrograde movement (PMID:19529763)
• Although DNAH1 is expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum. (PMID:24360805)
• variation in DNAH1 may play a role in primary ciliary dyskinesia (PMID:25927852)
• This mutation was distinct from previously reported DNAH1 mutations associated with MMAF and only affected the East Asian group. Furthermore, the variant DNAH1 protein could not be detected in spermatozoa by Western blot or immunofluorescence staining although DNAH1 mRNA was expressed in the spermatozoa. (PMID:27573432)
• Pedigree analysis supported the notion that the combination of DNAH1 gene mutations 52430998CCT>C and 52409336C>T and 52428484G>T alone were associated with MMAF. CONCLUSION(S): These DNAH1 gene mutations may be associated with DFS and infertility in the Han population. (PMID:28577616)
• DNAH1 variations were identified in 6 of 287 patients, including 8 heterozygous variations in exons and a splicing site. 4 variations (g.52400764G>C, g.52409336C>T, g.52430999_52431000del, g.52412624C>A) had already been registered in the 1000 Genomes and Exome Aggregation Consortium databases. The other novel variations (g.52418050del, g.52404762T>G, g.52430536del, g.52412620del) were all predicted to be pathogenic. (PMID:30544445)
• Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection. (PMID:32124190)
• Mutational landscape of DNAH1 in Chinese patients with multiple morphological abnormalities of the sperm flagella: cohort study and literature review. (PMID:33929677)
• Novel Biallelic DNAH1 Variations Cause Multiple Morphological Abnormalities of the Sperm Flagella. (PMID:33989052)
• Novel Loss-of-Function Mutations in DNAH1 Displayed Different Phenotypic Spectrum in Humans and Mice. (PMID:34867808)
• Novel compound heterozygous mutations in DNAH1 cause primary infertility in Han Chinese males with multiple morphological abnormalities of the sperm flagella. (PMID:36510862)
• Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males. (PMID:37302001)
• Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function. (PMID:37934199)
• Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. (PMID:39056782)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnah1	ENSDARG00000100115
mus_musculus	Dnah1	ENSMUSG00000019027
rattus_norvegicus	Dnah1	ENSRNOG00000026914
drosophila_melanogaster	sac	FBGN0037254

Paralogs (15): DNAH9 (ENSG00000007174), DNAH5 (ENSG00000039139), DNAH11 (ENSG00000105877), DNAH6 (ENSG00000115423), DNAH7 (ENSG00000118997), DNAH8 (ENSG00000124721), DNAH3 (ENSG00000158486), DNAH12 (ENSG00000174844), DNHD1 (ENSG00000179532), DNAH2 (ENSG00000183914), DNAH14 (ENSG00000185842), DYNC2H1 (ENSG00000187240), DNAH17 (ENSG00000187775), DYNC1H1 (ENSG00000197102), DNAH10 (ENSG00000197653)

Protein

Protein identifiers

Dynein axonemal heavy chain 1 — Q9P2D7 (reviewed: Q9P2D7)

Alternative names: Axonemal beta dynein heavy chain 1, Ciliary dynein heavy chain 1, Heat shock regulated protein 1, hDHC7

All UniProt accessions (4): Q9P2D7, A0A140VJI6, H7C506, H7C563

UniProt curated annotations — full annotation on UniProt →

Function. Force generating protein of cilia required for sperm flagellum motility. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Required in spermatozoa for the formation of the inner dynein arms and biogenesis of the axoneme.

Subunit / interactions. Consists of at least two heavy chains and a number of intermediate and light chains. Interacts with DNAH12.

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

Tissue specificity. Expressed primarily in trachea and testis, 2 tissues containing axonemal structures. Also expressed in brain.

Disease relevance. Spermatogenic failure 18 (SPGF18) [MIM:617576] An infertility disorder caused by spermatogenesis defects and characterized by abnormally shaped spermatozoa in the semen of affected individuals. SPGF18 patients present with primary infertility and multiple morphological abnormalities of sperm flagella that result in impaired sperm mobility. Abnormalities include absent, short, coiled, bent, and irregular flagella. SPGF18 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Ciliary dyskinesia, primary, 37 (CILD37) [MIM:617577] 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. Some patients exhibit randomization of left-right body asymmetry and situs inversus. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. CILD37 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Dynein heavy chains probably consist of an N-terminal stem (which binds cargo and interacts with other dynein components), and the head or motor domain. The motor contains six tandemly-linked AAA domains in the head, which form a ring. A stalk-like structure (formed by two of the coiled coil domains) protrudes between AAA 4 and AAA 5 and terminates in a microtubule-binding site. A seventh domain may also contribute to this ring; it is not clear whether the N-terminus or the C-terminus forms this extra domain. There are four well-conserved and two non-conserved ATPase sites, one per AAA domain. Probably only one of these (within AAA 1) actually hydrolyzes ATP, the others may serve a regulatory function.

Similarity. Belongs to the dynein heavy chain family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P2D7-4	4	yes
Q9P2D7-3	3
Q9P2D7-6	6
Q9P2D7-8	7

RefSeq proteins (1): NP_056327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004273	Dhc_D6_P-loop	Domain
IPR013602	Dhc_linker	Domain
IPR024317	Dhc_D4	Domain
IPR024743	Dynein_HC_stalk	Domain
IPR026983	DHC	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035699	Dhc_AAA	Domain
IPR035706	AAA_9	Domain
IPR041228	Dhc_C	Domain
IPR041466	Dhc_AAA5_ext	Domain
IPR041589	DNAH3_AAA_lid_1	Domain
IPR041658	AAA_lid_11	Domain
IPR042219	AAA_lid_11_sf	Homologous_superfamily
IPR042222	Dynein_2_N	Homologous_superfamily
IPR042228	Dynein_linker_3	Homologous_superfamily
IPR043157	Dynein_AAA1S	Homologous_superfamily
IPR043160	Dynein_C_barrel	Homologous_superfamily

Pfam: PF03028, PF08393, PF12774, PF12775, PF12777, PF12780, PF12781, PF17852, PF17857, PF18198, PF18199

UniProt features (73 total): sequence variant 24, sequence conflict 11, helix 11, region of interest 9, splice variant 6, binding site 4, short sequence motif 2, turn 2, chain 1, coiled-coil region 1, compositionally biased region 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8I3J	X-RAY DIFFRACTION	2.69
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

No AlphaFold model available for Q9P2D7 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 1581–1588; 1862–1869; 2227–2234; 2586–2593

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 190 (showing top): GOBP_MALE_GAMETE_GENERATION, GOBP_INNER_DYNEIN_ARM_ASSEMBLY, GOBP_AXONEMAL_DYNEIN_COMPLEX_ASSEMBLY, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOMF_CYTOSKELETAL_MOTOR_ACTIVITY, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, KEGG_HUNTINGTONS_DISEASE, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MOTILE_CILIUM_ASSEMBLY, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_AXONEME_ASSEMBLY

GO Biological Process (7): epithelial cilium movement involved in extracellular fluid movement (GO:0003351), sperm axoneme assembly (GO:0007288), flagellated sperm motility (GO:0030317), inner dynein arm assembly (GO:0036159), cilium-dependent cell motility (GO:0060285), microtubule-based movement (GO:0007018), cilium movement involved in cell motility (GO:0060294)

GO Molecular Function (6): microtubule motor activity (GO:0003777), ATP binding (GO:0005524), minus-end-directed microtubule motor activity (GO:0008569), dynein intermediate chain binding (GO:0045505), dynein light intermediate chain binding (GO:0051959), nucleotide binding (GO:0000166)

GO Cellular Component (12): extracellular region (GO:0005576), axonemal dynein complex (GO:0005858), microtubule (GO:0005874), axoneme (GO:0005930), dynein complex (GO:0030286), sperm flagellum (GO:0036126), inner dynein arm (GO:0036156), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), 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	4
cilium movement	3
cilium-dependent cell motility	2
protein binding	2
extracellular transport	1
microtubule-based transport	1
developmental process involved in reproduction	1
axoneme assembly	1
sperm flagellum assembly	1
cilium movement involved in cell motility	1
sperm motility	1
axonemal dynein complex assembly	1
cilium or flagellum-dependent cell motility	1
microtubule-based process	1
cell motility	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
ATP-dependent activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
microtubule motor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
axoneme	1
dynein complex	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
microtubule associated complex	1
catalytic complex	1
9+2 motile cilium	1
axonemal dynein complex	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

1668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAH1	DNAH12	Q6ZR08	954
DNAH1	M9MMK7	M9MMK7	934
DNAH1	CFAP43	Q8NDM7	782
DNAH1	CFAP44	Q96MT7	777
DNAH1	TTC29	Q8NA56	760
DNAH1	CFAP69	A5D8W1	701
DNAH1	ODAD1	Q96M63	696
DNAH1	QRICH2	Q9H0J4	686
DNAH1	TTC21A	Q8NDW8	669
DNAH1	CCDC39	Q9UFE4	664
DNAH1	FSIP2	Q5CZC0	655
DNAH1	CFAP251	Q8TBY9	652
DNAH1	CCDC40	Q4G0X9	651
DNAH1	DPY19L2	Q6NUT2	639
DNAH1	ARMC2	Q8NEN0	637

IntAct

10 interactions, top by confidence:

A	B	Type	Score
APP	APBB1	psi-mi:“MI:0914”(association)	0.910
APP	CRYAB	psi-mi:“MI:0914”(association)	0.670
DNAH1	H2AZ1	psi-mi:“MI:0915”(physical association)	0.400
DNAH1	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
DNAH1	H2BC12L	psi-mi:“MI:0915”(physical association)	0.400
DNAH1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): DNAH1 (Affinity Capture-RNA), DNAH1 (Affinity Capture-MS), DNAH1 (Affinity Capture-MS), DNAH1 (Affinity Capture-MS), DNAH1 (Proximity Label-MS), DNAH1 (Proximity Label-MS), DNAH1 (Proximity Label-MS), DNAH1 (Proximity Label-MS), DNAH1 (Affinity Capture-MS), MCM2 (Cross-Linking-MS (XL-MS)), HIST1H2BC (Cross-Linking-MS (XL-MS)), HIST1H2BD (Cross-Linking-MS (XL-MS)), HIST1H2BH (Cross-Linking-MS (XL-MS)), YARS (Cross-Linking-MS (XL-MS)), HIST1H3A (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2RRS8, A4D1B5, A5PLK6, D3Z6S9, E7FA21, G3UYX5, O75747, O75901, O88480, O88869, Q2T9P0, Q3UMB5, Q3UPC7, Q3URV1, Q402B2, Q4R9E9, Q5SUS0, Q5T0N1, Q5XI56, Q5XX13, Q642P2, Q6DHV5, Q6INI0, Q6P2C0, Q7L0X2, Q80X60, Q86VV8, Q86WZ0, Q8CDN1, Q8IV33, Q8IXR9, Q8K342, Q8N7B9, Q8N7X0, Q8ND61, Q8NE09, Q8NG48, Q8R4Y8, Q8TDY2, Q8TEV9

Diamond homologs: E9Q8T7, F1SC07, M0R8U1, P0C6F1, P23098, P39057, Q39565, Q39575, Q39610, Q3V0Q1, Q63164, Q63170, Q69Z23, Q6ZR08, Q8BW94, Q8IVF4, Q8TD57, Q8TE73, Q8VHE6, Q8WXX0, Q91XQ0, Q923J6, Q96DT5, Q96JB1, Q9C0G6, Q9MBF8, Q9NYC9, Q9P225, Q9P2D7, Q9SMH3, Q9UFH2, P84753, O75369, P80197, P87061, Q2R2W1, Q5Z8K3, Q67UX0, Q7M3S9, Q80X90

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2966 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	52
Uncertain significance	1363
Likely benign	1190
Benign	141

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033365	NM_015512.5(DNAH1):c.9352C>T (p.Arg3118Ter)	Pathogenic
1060963	NM_015512.5(DNAH1):c.7066C>T (p.Arg2356Trp)	Pathogenic
1068985	NM_015512.5(DNAH1):c.2921_2939dup (p.Arg981fs)	Pathogenic
1421082	NM_015512.5(DNAH1):c.2005_2014del (p.Gly669fs)	Pathogenic
1451711	NM_015512.5(DNAH1):c.3107G>A (p.Trp1036Ter)	Pathogenic
1455501	NM_015512.5(DNAH1):c.4167C>A (p.Tyr1389Ter)	Pathogenic
1459903	NM_015512.5(DNAH1):c.2602C>T (p.Arg868Ter)	Pathogenic
1905119	NM_015512.5(DNAH1):c.5547C>A (p.Tyr1849Ter)	Pathogenic
1914975	NM_015512.5(DNAH1):c.5308C>T (p.Arg1770Ter)	Pathogenic
1965274	NM_015512.5(DNAH1):c.7559C>G (p.Ser2520Ter)	Pathogenic
1988199	NM_015512.5(DNAH1):c.526C>T (p.Gln176Ter)	Pathogenic
2002471	NM_015512.5(DNAH1):c.2926del (p.Ala976fs)	Pathogenic
2021302	NM_015512.5(DNAH1):c.8626-1G>C	Pathogenic
2029087	NM_015512.5(DNAH1):c.202_203del (p.Pro68fs)	Pathogenic
2033207	NM_015512.5(DNAH1):c.7342del (p.Gln2448fs)	Pathogenic
2036895	NM_015512.5(DNAH1):c.3583C>T (p.Gln1195Ter)	Pathogenic
2105670	NM_015512.5(DNAH1):c.12029_12030insGT (p.Lys4011fs)	Pathogenic
2127419	NM_015512.5(DNAH1):c.5282_5283del (p.Val1761fs)	Pathogenic
2146566	NM_015512.5(DNAH1):c.7435C>T (p.Arg2479Ter)	Pathogenic
2151429	NM_015512.5(DNAH1):c.4284G>A (p.Trp1428Ter)	Pathogenic
2167601	NM_015512.5(DNAH1):c.8170C>T (p.Arg2724Ter)	Pathogenic
2170067	NM_015512.5(DNAH1):c.5206_5207del (p.Thr1736fs)	Pathogenic
2418996	NM_015512.5(DNAH1):c.171del (p.Lys58fs)	Pathogenic
2426175	NC_000003.11:g.(?52424931)(52427521_?)del	Pathogenic
2504099	NM_015512.5(DNAH1):c.2610G>A (p.Trp870Ter)	Pathogenic
2573286	NM_004656.4(BAP1):c.1228C>T (p.Gln410Ter)	Pathogenic
2923376	NM_015512.5(DNAH1):c.391A>T (p.Lys131Ter)	Pathogenic
2924067	NM_015512.5(DNAH1):c.10096C>T (p.Arg3366Ter)	Pathogenic
2924267	NM_015512.5(DNAH1):c.352C>T (p.Arg118Ter)	Pathogenic
2926627	NM_015512.5(DNAH1):c.5736C>G (p.Tyr1912Ter)	Pathogenic

SpliceAI

14094 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52326132:A:AG	acceptor_gain	1.0000
3:52326132:ACCT:A	acceptor_gain	1.0000
3:52326133:C:G	acceptor_gain	1.0000
3:52326135:T:TA	acceptor_gain	1.0000
3:52326138:A:AG	acceptor_gain	1.0000
3:52326138:AGTC:A	acceptor_gain	1.0000
3:52326138:AGTCG:A	acceptor_gain	1.0000
3:52326139:G:GC	acceptor_gain	1.0000
3:52326139:GT:G	acceptor_gain	1.0000
3:52326139:GTC:G	acceptor_gain	1.0000
3:52326139:GTCG:G	acceptor_gain	1.0000
3:52326139:GTCGG:G	acceptor_gain	1.0000
3:52326312:GAG:G	donor_gain	1.0000
3:52326313:AG:A	donor_loss	1.0000
3:52326314:GG:G	donor_loss	1.0000
3:52326315:G:C	donor_loss	1.0000
3:52326316:T:A	donor_loss	1.0000
3:52327222:GG:G	donor_gain	1.0000
3:52327223:GG:G	donor_gain	1.0000
3:52327876:TTCCA:T	acceptor_loss	1.0000
3:52327877:TCCAG:T	acceptor_loss	1.0000
3:52327879:CAGGT:C	acceptor_loss	1.0000
3:52327880:A:AC	acceptor_loss	1.0000
3:52327881:G:T	acceptor_loss	1.0000
3:52327962:G:GT	donor_gain	1.0000
3:52327963:A:T	donor_gain	1.0000
3:52331146:A:AG	acceptor_gain	1.0000
3:52331146:AGAG:A	acceptor_gain	1.0000
3:52331147:G:GG	acceptor_gain	1.0000
3:52331147:GA:G	acceptor_gain	1.0000

AlphaMissense

28311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52361299:C:G	C1607W	1.000
3:52361671:T:A	W1629R	1.000
3:52361671:T:C	W1629R	1.000
3:52361683:G:C	D1633H	1.000
3:52361684:A:C	D1633A	1.000
3:52361684:A:G	D1633G	1.000
3:52361684:A:T	D1633V	1.000
3:52361686:G:A	E1634K	1.000
3:52361687:A:T	E1634V	1.000
3:52361694:T:A	N1636K	1.000
3:52361694:T:G	N1636K	1.000
3:52368838:T:A	W1955R	1.000
3:52368838:T:C	W1955R	1.000
3:52352637:T:C	L986P	0.999
3:52352676:G:C	R999P	0.999
3:52353152:T:C	L1026P	0.999
3:52353154:T:A	W1027R	0.999
3:52353154:T:C	W1027R	0.999
3:52361253:A:T	K1592I	0.999
3:52361254:A:C	K1592N	0.999
3:52361254:A:T	K1592N	0.999
3:52361296:C:A	N1606K	0.999
3:52361296:C:G	N1606K	0.999
3:52361297:T:C	C1607R	0.999
3:52361342:G:C	G1622R	0.999
3:52361343:G:A	G1622D	0.999
3:52361675:C:A	A1630D	0.999
3:52361679:C:G	C1631W	0.999
3:52361683:G:A	D1633N	0.999
3:52361683:G:T	D1633Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000003594 (3:52373224 G>A), RS1000016059 (3:52359734 G>A), RS1000034266 (3:52341974 T>C), RS1000080169 (3:52331767 G>A,C), RS1000103698 (3:52367370 G>A), RS1000147347 (3:52379083 G>A), RS1000186501 (3:52389415 CTG>C), RS1000223388 (3:52339519 A>T), RS1000258617 (3:52389690 C>T), RS1000326228 (3:52345762 C>A), RS1000342762 (3:52311972 C>T), RS1000364311 (3:52384443 G>A), RS1000396029 (3:52355570 C>G), RS1000402123 (3:52373795 A>G), RS1000419636 (3:52395937 CCTTT>C)

Disease associations

OMIM: gene MIM:603332 | disease phenotypes: MIM:617577, MIM:617576, MIM:244400, MIM:614327, MIM:606763, MIM:611884, MIM:258150, MIM:616589

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 18	Strong	Autosomal recessive
ciliary dyskinesia, primary, 37	Strong	Autosomal recessive
primary ciliary dyskinesia 7	Moderate	Autosomal recessive
primary ciliary dyskinesia	Supportive	Autosomal dominant
non-syndromic male infertility due to sperm motility disorder	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
spermatogenic failure 18	Definitive	AR
primary ciliary dyskinesia	Limited	AR

Mondo (16): ciliary dyskinesia, primary, 37 (MONDO:0033204), spermatogenic failure 18 (MONDO:0054615), primary ciliary dyskinesia (MONDO:0016575), primary ciliary dyskinesia 1 (MONDO:0009484), intellectual disability (MONDO:0001071), BAP1-related tumor predisposition syndrome (MONDO:0013692), hereditary neoplastic syndrome (MONDO:0015356), familial melanoma (MONDO:0018961), oligospermia (MONDO:0001913), primary ciliary dyskinesia 2 (MONDO:0011718), primary ciliary dyskinesia 7 (MONDO:0012748), premature menopause (MONDO:0001119), spermatogenic failure 1 (MONDO:0009776), congenital portosystemic shunt (MONDO:0018811), Adams-Oliver syndrome 6 (MONDO:0014703)

Orphanet (9): Primary ciliary dyskinesia (Orphanet:244), Inherited cancer-predisposing syndrome (Orphanet:140162), BAP1-related tumor predisposition syndrome (Orphanet:289539), Familial melanoma (Orphanet:618), Congenital portosystemic shunt (Orphanet:480531), Adams-Oliver syndrome (Orphanet:974), Non-syndromic male infertility due to sperm motility disorder (Orphanet:276234), Primary ciliary dyskinesia, Kartagener type (Orphanet:98861), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

60 total (30 of 60 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:0000821	Hypothyroidism
HP:0000853	Goiter
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:0002110	Bronchiectasis
HP:0002119	Ventriculomegaly
HP:0002257	Chronic rhinitis
HP:0002566	Intestinal malrotation
HP:0002643	Neonatal respiratory distress
HP:0002878	Respiratory failure
HP:0003251	Male infertility
HP:0005301	Persistent left superior vena cava

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST002709_14	Electroencephalogram traits	9.000000e-06
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004902_20	Parkinson’s disease	3.000000e-08
GCST006611_1	HDL cholesterol	2.000000e-14
GCST007576_378	Chronotype	3.000000e-12
GCST012490_243	Femur bone mineral density x serum urate levels interaction	9.000000e-10
GCST90020025_1957	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST90020025_1958	Waist-to-hip ratio adjusted for BMI	5.000000e-08
GCST90020027_115	Waist-hip index	1.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0006870	alpha wave measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008328	chronotype measurement
EFO:0004531	urate measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508
C567504	Ciliary Dyskinesia, Primary, 7 (supp.)
C562902	Oligosynaptic Infertility (supp.)
C535277	Primary ciliary dyskinesia, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
bisphenol A	decreases expression, increases expression, affects cotreatment	2
sodium arsenite	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
benzo(e)pyrene	affects methylation, decreases methylation, increases methylation	1
aflatoxin B2	decreases methylation, increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	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
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Haloperidol	decreases expression, affects cotreatment	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Mercury	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
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