DYNC1H1

Summary

DYNC1H1 (dynein cytoplasmic 1 heavy chain 1, HGNC:2961) is a protein-coding gene on chromosome 14q32.31, encoding Cytoplasmic dynein 1 heavy chain 1 (Q14204). Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family.

Source: NCBI Gene 1778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete neuronopathy, distal hereditary motor (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 5,617 total — 36 pathogenic, 126 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001376

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2961
Approved symbol	DYNC1H1
Name	dynein cytoplasmic 1 heavy chain 1
Location	14q32.31
Locus type	gene with protein product
Status	Approved
Aliases	Dnchc1, HL-3, p22, DHC1, CMT2O
Ensembl gene	ENSG00000197102
Ensembl biotype	protein_coding
OMIM	600112
Entrez	1778

Gene structure

Transcript identifiers

Ensembl transcripts: 65 — 31 retained_intron, 24 nonsense_mediated_decay, 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000360184, ENST00000554854, ENST00000555062, ENST00000555800, ENST00000556139, ENST00000556229, ENST00000556499, ENST00000642716, ENST00000642882, ENST00000643279, ENST00000643437, ENST00000643508, ENST00000643565, ENST00000643591, ENST00000643684, ENST00000643722, ENST00000643729, ENST00000643764, ENST00000643829, ENST00000643958, ENST00000644206, ENST00000644239, ENST00000644794, ENST00000644881, ENST00000644888, ENST00000645039, ENST00000645085, ENST00000645114, ENST00000645149, ENST00000645697, ENST00000645978, ENST00000646418, ENST00000647119, ENST00000647143, ENST00000647204, ENST00000647307, ENST00000647366, ENST00000679486, ENST00000679629, ENST00000679720, ENST00000679910, ENST00000680001, ENST00000680120, ENST00000680137, ENST00000680178, ENST00000680200, ENST00000680313, ENST00000680423, ENST00000680715, ENST00000680808, ENST00000680874, ENST00000681010, ENST00000681066, ENST00000681123, ENST00000681283, ENST00000681311, ENST00000681321, ENST00000681536, ENST00000681574, ENST00000681668, ENST00000681751, ENST00000681822, ENST00000681859, ENST00000684561, ENST00000919473

RefSeq mRNA: 1 — MANE Select: NM_001376 NM_001376

CCDS: CCDS9966

Canonical transcript exons

ENST00000360184 — 78 exons

Exon	Start	End
ENSE00000452675	102002792	102002965
ENSE00000452677	102004762	102004950
ENSE00000660405	101994673	101994849
ENSE00000660408	101995181	101995300
ENSE00000660409	101997035	101997274
ENSE00000660410	101999989	102000144
ENSE00000660411	102000286	102000399
ENSE00000660412	102000954	102001064
ENSE00000660416	102002537	102002703
ENSE00000660421	102005888	102006170
ENSE00000660423	102008178	102008337
ENSE00000660429	102017383	102017504
ENSE00000870429	102017088	102017294
ENSE00000870430	102018451	102018616
ENSE00000870434	102027174	102027288
ENSE00000870435	102027383	102027544
ENSE00000870436	102027619	102027833
ENSE00000870439	102029819	102029938
ENSE00000870440	102030162	102030282
ENSE00000870441	102032272	102032467
ENSE00000870442	102033065	102033182
ENSE00000870455	102043875	102044045
ENSE00000870456	102044274	102044491
ENSE00000870457	102044595	102044698
ENSE00000870458	102047817	102048028
ENSE00000870460	102049440	102049582
ENSE00000870461	102049714	102049882
ENSE00000941433	102001535	102001681
ENSE00000941441	102016766	102016999
ENSE00001099815	102019893	102020056
ENSE00001153297	102042384	102042507
ENSE00001153304	102042228	102042288
ENSE00001153309	102042013	102042124
ENSE00001153329	102039638	102039732
ENSE00001153335	102039412	102039546
ENSE00001153342	102039001	102039254
ENSE00001153351	102038460	102038606
ENSE00001153531	102005042	102005236
ENSE00001153541	102004518	102004683
ENSE00001153607	101994986	101995096
ENSE00001153624	101994184	101994324
ENSE00001153709	101964573	101964947
ENSE00001225972	102009843	102010086
ENSE00001306171	102007008	102007108
ENSE00001335254	102016349	102016489
ENSE00001335256	102015856	102016086
ENSE00001335258	102015105	102015332
ENSE00001335260	102012314	102012470
ENSE00001335262	102011875	102012113
ENSE00001335263	102010740	102010952
ENSE00001335264	102010276	102010459
ENSE00001335270	101991527	101991673
ENSE00001335271	101988703	101988852
ENSE00001335272	101987453	101987632
ENSE00001335274	101985687	101986763
ENSE00001335277	101983382	101983609
ENSE00001335281	101983019	101983290
ENSE00001335349	101980364	101980550
ENSE00001335350	101979719	101979974
ENSE00001335352	101979319	101979492
ENSE00001335354	101975712	101975799
ENSE00001397574	102001145	102001354
ENSE00003463797	102034325	102034452
ENSE00003483757	102042635	102042748
ENSE00003489301	102029539	102029712
ENSE00003505476	102027937	102028141
ENSE00003516546	102038698	102038848
ENSE00003526273	102033269	102033484
ENSE00003549773	102048516	102048669
ENSE00003560378	102022751	102022880
ENSE00003560503	102041574	102041734
ENSE00003595064	102026574	102026707
ENSE00003610465	102050071	102050198
ENSE00003660248	102040236	102040410
ENSE00003665703	102040598	102040673
ENSE00003690612	102033976	102034188
ENSE00003691993	102036489	102036642
ENSE00003829614	102050435	102056443

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.4900 / max 673.7997, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141632	59.5231	1823
141633	14.4500	1803
141631	9.3181	1762
141636	0.1989	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.52	gold quality
ganglionic eminence	UBERON:0004023	99.42	gold quality
ventricular zone	UBERON:0003053	99.39	gold quality
prefrontal cortex	UBERON:0000451	99.30	gold quality
stromal cell of endometrium	CL:0002255	99.28	gold quality
right frontal lobe	UBERON:0002810	99.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.23	gold quality
cerebellar hemisphere	UBERON:0002245	99.22	gold quality
cerebellar cortex	UBERON:0002129	99.12	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.08	gold quality
postcentral gyrus	UBERON:0002581	99.04	gold quality
cerebellum	UBERON:0002037	99.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.00	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.96	gold quality
colonic epithelium	UBERON:0000397	98.92	gold quality
frontal cortex	UBERON:0001870	98.90	gold quality
substantia nigra pars compacta	UBERON:0001965	98.89	gold quality
parietal lobe	UBERON:0001872	98.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.88	gold quality
dorsal root ganglion	UBERON:0000044	98.82	gold quality
neocortex	UBERON:0001950	98.82	gold quality
amygdala	UBERON:0001876	98.81	gold quality
cerebral cortex	UBERON:0000956	98.77	gold quality
apex of heart	UBERON:0002098	98.76	gold quality
adrenal tissue	UBERON:0018303	98.75	gold quality
calcaneal tendon	UBERON:0003701	98.74	gold quality
nucleus accumbens	UBERON:0001882	98.73	gold quality
telencephalon	UBERON:0001893	98.72	gold quality
Ammon’s horn	UBERON:0001954	98.70	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7249	no	17361.85
E-HCAD-6	no	716.74
E-MTAB-7606	no	566.34
E-HCAD-5	no	8.34
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, FOS, JUN, NFKB, RELA, SMARCA1, TP53, TP63, TXK

miRNA regulators (miRDB)

13 targeting DYNC1H1, 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-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-10526-3P	97.86	64.97	1342

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• mediates the perinuclear aggregation of phagocytosed melanosomes, participates in the formation of the supranuclear melanin cap or “microparasol” and serves as a mechanism to help protect the nucleus from ultraviolet-induced DNA damage. (PMID:14632200)
• these results suggest that complexes of dynein, Lis1 and CLIP-170 crosslink and slide microtubules within the spindle, thereby producing an inward force that pulls centrosomes together. (PMID:19020519)
• In an in vitro MT gliding assay, both dynein-1 and dynein-2 showed minus-end-directed motor activities. (PMID:21723285)
• Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1. (PMID:21820100)
• Mutations in DYNC1H1 can lead to a broad phenotypic spectrum, confirming the importance of DYNC1H1 in both central and peripheral neuronal functions. (PMID:22368300)
• Studies indicate that binding of dynactin, LIS1 and NudEL regulate cytoplasmic dynein motor activity. (PMID:22373868)
• study demonstrates that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a DYNC1H1 mutation disrupts dynein complex assembly and function (PMID:22459677)
• this study has demonstrated that the same DYNC1H1 mutation could cause spinal muscular atrophy as well as distal neuropathy, indicating pleotropic effects of the mutation. (PMID:22847149)
• LIS1 is required for dynein-mediated transport induced by membrane tethering of BICD2-N and LIS1 contributes to dynein accumulation at microtubule plus ends and BICD2-positive cellular structures. (PMID:22956769)
• analysis of reconstitution of the human cytoplasmic dynein complex (PMID:23213255)
• Data indicate that dynein- and astral microtubule-mediated transport of Galphai/LGN/nuclear mitotic apparatus (NuMA) complex from cell cortex to spindle poles. (PMID:23389635)
• The cytoplasmic Dynein Heavy Chain 1 (DHC) was found to interact with NF1 along microtubules in vesicular structures identified to be melanosomes. (PMID:23583712)
• Dynein forms distinct complexes requiring specific recruiters and activators to promote orderly progression through mitosis. (PMID:23589491)
• This study demonistrated that Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age. (PMID:23742762)
• It focus on cytoplasmic dynein, which is required for a myriad of cellular functions in interphase, mitosis and meiosis, ranging from transport of organelles and functioning of the mitotic spindle to chromosome movements in meiotic prophase. (PMID:24256283)
• Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems. (PMID:24307404)
• In conclusion, association with microtubules and the translocation activity of dynein motor complexes are required to achieve efficient retrovirus restriction by TRIM5alpha. (PMID:24600008)
• Authors propose that Snapin connects chlamydial inclusions with the microtubule network by interacting with both Chlamydia psittaci IncB and dynein. (PMID:24751478)
• This study demonistrated that DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy. (PMID:24755273)
• Dynactin functions as both a dynamic tether and brake during dynein-driven motility. (PMID:25185702)
• Authors find that pharmacological or small interfering RNA (siRNA)-mediated inhibition of cytoplasmic dynein or the kinesin 1 heavy chain KIF5B delays HIV-1 uncoating. (PMID:25231297)
• single dynein molecules in the cell are autoinhibited through intramolecular head-head stacking (PMID:25266423)
• These results reveal that conformational changes involving hexon hypervariable region 1 are the basis for a novel viral mechanism controlling capsid transport to the nucleus by dynein. (PMID:25355895)
• These findings also reveal a possible new target for Amblyomin-X, i.e., dynein, and may serve as a tool for investigating tumor cell death associated with proteasome inhibition. (PMID:25479096)
• The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. (PMID:25512093)
• Report expands the clinical spectrum of DYNC1H1-related spinal muscular atrophy to include generalized arthrogryposis (PMID:25609763)
• Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. (PMID:26100331)
• A novel de novo mutation (c.2327C > T, p.P776L) in the DYNC1H1 gene identified and confirmed it as the causal variant of Spinal muscular atrophy with lower extremity predominance. (PMID:26846447)
• These results suggest that cytoplasmic dynein 1 binds to BRCA2 through the latter’s centrosomal localization signal and BRCA2 mediates the cohesion between centrosomes during the S phase, potentially serving as a cell-cycle checkpoint. (PMID:27433848)
• This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. (PMID:28196890)
• Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of epileptic encephalopathies. (PMID:28325891)
• Structural and functional mutations and hotspots for DYNC1H1. (PMID:28455235)
• This cohort demonstrates that mutations in DYNC1H1 can mimic a congenital myopathy. (PMID:28554554)
• Here, the authors use quantitative imaging and laser ablation to show that NuMA targets dynactin to spindle microtubule minus-ends, localizing dynein activity there. (PMID:29185983)
• Over the years other phenotypes including Charcot Marie Tooth type 2 and hereditary mental retardation with cortical neural migration defects have also been reported to be caused by DYNC1H1 mutations (PMID:29306600)
• Using in vitro total internal reflection fluorescence microscopy, the study observed that higher concentrations of Ndc80 inhibited dynein binding to microtubules, providing evidence that Ndc80 and dynein antagonize each other’s function. (PMID:29475948)
• Significantly decreased methylation of CpG islands within exon 37 of the DYNC1H1 gene was observed in patients with a severe SMA manifestation (type I) compared to mildly affected SMA patients (types III-IV). (PMID:30246859)
• Acting like a sponge of miR-140-5p, silenced circDYNC1H1 downregulated SULT2B1 to restrain HCC cell proliferation. (PMID:30864145)
• A High-Throughput Cellular Screening Assay for Small-Molecule Inhibitors and Activators of Cytoplasmic Dynein-1-Based Cargo Transport. (PMID:32436764)
• DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants. (PMID:32656949)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dync1h1	ENSDARG00000014717
mus_musculus	Dync1h1	ENSMUSG00000018707
rattus_norvegicus	Dync1h1	ENSRNOG00000006178
drosophila_melanogaster	Dhc64C	FBGN0261797
caenorhabditis_elegans	dhc-1	WBGENE00000962

Paralogs (15): DNAH9 (ENSG00000007174), DNAH5 (ENSG00000039139), DNAH11 (ENSG00000105877), DNAH1 (ENSG00000114841), DNAH6 (ENSG00000115423), DNAH7 (ENSG00000118997), DNAH8 (ENSG00000124721), DNAH3 (ENSG00000158486), DNAH12 (ENSG00000174844), DNHD1 (ENSG00000179532), DNAH2 (ENSG00000183914), DNAH14 (ENSG00000185842), DYNC2H1 (ENSG00000187240), DNAH17 (ENSG00000187775), DNAH10 (ENSG00000197653)

Protein

Protein identifiers

Cytoplasmic dynein 1 heavy chain 1 — Q14204 (reviewed: Q14204)

Alternative names: Cytoplasmic dynein heavy chain 1, Dynein heavy chain, cytosolic

All UniProt accessions (32): A0A2R8Y5T0, A0A2R8Y6H2, A0A2R8Y706, A0A2R8YFZ7, A0A2R8YGC7, A0A7P0T7V5, A0A7P0T825, A0A7P0T8N2, A0A7P0T8W5, A0A7P0T916, A0A7P0T934, A0A7P0T942, A0A7P0T990, A0A7P0T9C4, A0A7P0T9F1, A0A7P0T9K2, A0A7P0T9R4, A0A7P0T9S3, A0A7P0T9Y3, A0A7P0TA13, A0A7P0TAF3, A0A7P0TAM4, A0A7P0TAS7, A0A7P0TAV5, A0A7P0TAW9, A0A7P0TB64, A0A7P0TB75, A0A7P0TB96, A0A7P0TBC9, A0A7P0TBJ7, A0A804HHY6, Q14204

UniProt curated annotations — full annotation on UniProt →

Function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Plays a role in mitotic spindle assembly and metaphase plate congression.

Subunit / interactions. Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and dynein LCs assemble on the IC dimer. Interacts with DYNC1LI1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1LI2; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1I2. Interacts with BICD2. Interacts with isoform 2 of CRACR2A. Interacts with DNALI1.

Subcellular location. Cytoplasm. Cytoskeleton.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2O (CMT2O) [MIM:614228] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Cortical dysplasia, complex, with other brain malformations 13 (CDCBM13) [MIM:614563] An autosomal dominant disorder characterized by global developmental delay with impaired intellectual development. Some patients show signs of peripheral neuropathy, such as abnormal gait and hyporeflexia. CDCBM13 is associated with variable neuronal migration defects resulting in cortical malformations. The disease is caused by variants affecting the gene represented in this entry. Spinal muscular atrophy, lower extremity-predominant 1, autosomal dominant (SMALED1) [MIM:158600] A form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMALED1 is characterized by muscle weakness predominantly affecting the proximal lower extremities. 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.

RefSeq proteins (1): NP_001367* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR004273	Dhc_D6_P-loop	Domain
IPR013594	Dynein_heavy_tail	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
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
IPR054354	DYNC2H1-like_lid	Domain

Pfam: PF03028, PF08385, PF08393, PF12774, PF12775, PF12777, PF12780, PF12781, PF17852, PF18198, PF18199, PF22597

UniProt features (384 total): helix 178, strand 102, turn 36, sequence variant 31, region of interest 11, modified residue 9, coiled-coil region 8, binding site 4, sequence conflict 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

97 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5OWO	X-RAY DIFFRACTION	1.79
9BLZ	ELECTRON MICROSCOPY	2.2
9BMR	ELECTRON MICROSCOPY	2.6
9DH5	ELECTRON MICROSCOPY	2.6
9E0X	ELECTRON MICROSCOPY	2.7
9E10	ELECTRON MICROSCOPY	2.71
9BM0	ELECTRON MICROSCOPY	2.8
9BMF	ELECTRON MICROSCOPY	2.8
9BMH	ELECTRON MICROSCOPY	2.8
9BN3	ELECTRON MICROSCOPY	2.8
9BM2	ELECTRON MICROSCOPY	2.82
9BMG	ELECTRON MICROSCOPY	2.86
9BMY	ELECTRON MICROSCOPY	2.86
9E0Z	ELECTRON MICROSCOPY	2.86
9E11	ELECTRON MICROSCOPY	2.86
8FD6	ELECTRON MICROSCOPY	2.9
9BMD	ELECTRON MICROSCOPY	2.9
9BN4	ELECTRON MICROSCOPY	2.9
9BMZ	ELECTRON MICROSCOPY	2.97
9BM1	ELECTRON MICROSCOPY	3.02
9BMS	ELECTRON MICROSCOPY	3.04
9BMJ	ELECTRON MICROSCOPY	3.1
9BMM	ELECTRON MICROSCOPY	3.1
9DZY	ELECTRON MICROSCOPY	3.1
9E0T	ELECTRON MICROSCOPY	3.1
8FDT	ELECTRON MICROSCOPY	3.2
9BMA	ELECTRON MICROSCOPY	3.2
9E0K	ELECTRON MICROSCOPY	3.2
9E0W	ELECTRON MICROSCOPY	3.2
9BM6	ELECTRON MICROSCOPY	3.22

Predicted structure (AlphaFold)

No AlphaFold model available for Q14204 — 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): 1906–1913; 2224–2231; 2595–2602; 2937–2944

Post-translational modifications (9): 2, 70, 1125, 1230, 3480, 4162, 4283, 4366, 4368

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2132295	MHC class II antigen presentation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-380259	Loss of Nlp from mitotic centrosomes
R-HSA-380270	Recruitment of mitotic centrosome proteins and complexes
R-HSA-380284	Loss of proteins required for interphase microtubule organization from the centrosome
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-6798695	Neutrophil degranulation
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-68877	Mitotic Prometaphase
R-HSA-8854518	AURKA Activation by TPX2
R-HSA-9609690	HCMV Early Events
R-HSA-9646399	Aggrephagy
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation

MSigDB gene sets: 412 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GCM_MAP4K4, AP1_01, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_P_BODY_ASSEMBLY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_AXO_DENDRITIC_TRANSPORT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOCC_SECRETORY_GRANULE, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION

GO Biological Process (14): mitotic spindle organization (GO:0007052), nuclear migration (GO:0007097), retrograde axonal transport (GO:0008090), cytoplasmic microtubule organization (GO:0031122), positive regulation of intracellular transport (GO:0032388), P-body assembly (GO:0033962), stress granule assembly (GO:0034063), establishment of spindle localization (GO:0051293), cell division (GO:0051301), regulation of mitotic spindle organization (GO:0060236), regulation of metaphase plate congression (GO:0090235), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of spindle assembly (GO:1905832), microtubule-based movement (GO:0007018)

GO Molecular Function (9): RNA binding (GO:0003723), ATP binding (GO:0005524), minus-end-directed microtubule motor activity (GO:0008569), identical protein binding (GO:0042802), dynein intermediate chain binding (GO:0045505), dynein light intermediate chain binding (GO:0051959), nucleotide binding (GO:0000166), protein binding (GO:0005515), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (15): extracellular region (GO:0005576), centrosome (GO:0005813), cytosol (GO:0005829), cytoplasmic dynein complex (GO:0005868), microtubule (GO:0005874), cytoplasmic microtubule (GO:0005881), cell cortex (GO:0005938), membrane (GO:0016020), filopodium (GO:0030175), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), axon cytoplasm (GO:1904115), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), dynein complex (GO:0030286)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Mitotic Prometaphase	3
G2/M Transition	2
Centrosome maturation	2
Amplification of signal from the kinetochores	1
Adaptive Immune System	1
Mitotic Anaphase	1
Cellular responses to stress	1
Loss of proteins required for interphase microtubule organization from the centrosome	1
Assembly of the 9+0 primary cilium	1
RHO GTPase Effectors	1
Innate Immune System	1
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1
M Phase	1
HCMV Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	3
cytoplasm	3
intracellular transport	2
establishment of organelle localization	2
microtubule cytoskeleton organization	2
membraneless organelle assembly	2
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
nucleus localization	1
axonal transport	1
axon cytoplasm	1
supramolecular fiber organization	1
regulation of intracellular transport	1
positive regulation of cellular process	1
positive regulation of transport	1
establishment of localization in cell	1
spindle localization	1
cellular process	1
mitotic spindle organization	1
regulation of spindle organization	1
regulation of localization	1
metaphase chromosome alignment	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
spindle assembly	1
positive regulation of cytoskeleton organization	1
positive regulation of cell cycle process	1
regulation of spindle assembly	1
positive regulation of organelle assembly	1
microtubule-based process	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
microtubule motor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1

Protein interactions and networks

STRING

3026 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DYNC1H1	DYNC1LI2	O43237	982
DYNC1H1	DYNC1I1	O14576	966
DYNC1H1	DYNC1I2	Q13409	929
DYNC1H1	DYNC1LI1	Q9Y6G9	922
DYNC1H1	DCTN6	O00399	918
DYNC1H1	DCTN5	Q9BTE1	910
DYNC1H1	DYNLL1	P63167	899
DYNC1H1	DCTN1	Q14203	892
DYNC1H1	NUDC	Q9Y266	869
DYNC1H1	DCTN2	Q13561	807
DYNC1H1	NUDCD3	Q8IVD9	781
DYNC1H1	DYNLRB1	Q9NP97	770
DYNC1H1	TUBG1	P23258	758
DYNC1H1	KIF5C	O60282	734
DYNC1H1	BICD2	Q8TD16	723

IntAct

460 interactions, top by confidence:

A	B	Type	Score
HTT	DYNC1H1	psi-mi:“MI:0915”(physical association)	0.770
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DYNC1I2	DYNC1LI2	psi-mi:“MI:0914”(association)	0.680
DYNLT1	DYNC1LI2	psi-mi:“MI:0914”(association)	0.640
DYNC1H1	ASPH	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	CDK8	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	CFL2	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	COX4I1	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	CRYBB3	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	CTSH	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	GADD45A	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	IL16	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	MAP3K5	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	PPP1R12B	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	NEUROG1	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	NTF3	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	OTX2	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	POLR2E	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	MAPK11	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	RXRG	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	TCAP	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	EIF2B5	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	BAG3	psi-mi:“MI:0915”(physical association)	0.560
DYNC1H1	BZW1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (729): DYNC1H1 (Affinity Capture-Western), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-Western), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-RNA), DCTN1 (Co-fractionation), DYNC1H1 (Co-fractionation)

ESM2 similar proteins: A0A1B0GVH7, A2RRP1, D3YVL2, E9Q8T7, O55007, O88480, P0C6F1, P37276, P38650, Q0KK59, Q14204, Q3UHQ6, Q3UMB5, Q3V0Q1, Q4R7B1, Q5R414, Q5SQX6, Q5T0N1, Q5ZLS8, Q63164, Q63170, Q642P2, Q69Z23, Q6GYP7, Q6GYQ0, Q6ZR08, Q7L576, Q7TMB8, Q8BW94, Q8IVF4, Q8K2A7, Q8TD57, Q8TDY2, Q8TEV9, Q8WVF1, Q8WXX0, Q91XQ0, Q923J6, Q95LN2, Q96F07

Diamond homologs: P34036, P37276, P38650, P39057, P45443, P45444, P78716, Q14204, Q19020, Q27171, Q8IBG1, Q9C1M7, Q9JHU4, Q3V0Q1, Q923J6, P36022, Q9SMH5, Q96DT5, Q6ZR08, E9Q8T7, M0R8U1, Q0VDD8, Q39610, Q63164, Q63170, Q8BW94, Q8TD57, Q8WXX0, Q9C0G6, Q9P2D7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
INTS4	“up-regulates quantity”	DYNC1H1
PAFAH1B1	“up-regulates activity”	DYNC1H1	binding
NDEL1	“up-regulates activity”	DYNC1H1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 164 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
COPI-independent Golgi-to-ER retrograde traffic	10	20.0×	4e-08
Aggrephagy	8	19.1×	1e-06
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	8	14.9×	4e-06
Loss of Nlp from mitotic centrosomes	9	13.7×	2e-06
Loss of proteins required for interphase microtubule organization from the centrosome	9	13.7×	2e-06
AURKA Activation by TPX2	9	13.2×	2e-06
Anchoring of the basal body to the plasma membrane	12	13.1×	4e-08
Recruitment of NuMA to mitotic centrosomes	11	12.3×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment of mitotic spindle orientation	6	20.9×	2e-04
microtubule-based movement	7	15.0×	2e-04
microtubule cytoskeleton organization	10	8.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

5617 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	126
Uncertain significance	2146
Likely benign	2508
Benign	197

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1053168	NM_001376.5(DYNC1H1):c.5035C>T (p.Arg1679Trp)	Pathogenic
1200540	NM_001376.5(DYNC1H1):c.2906T>C (p.Ile969Thr)	Pathogenic
1212893	NM_001376.5(DYNC1H1):c.5705G>T (p.Gly1902Val)	Pathogenic
1520504	NM_001376.5(DYNC1H1):c.1396A>G (p.Met466Val)	Pathogenic
162033	NM_001376.5(DYNC1H1):c.791G>T (p.Arg264Leu)	Pathogenic
1685755	NM_001376.5(DYNC1H1):c.3395G>A (p.Gly1132Glu)	Pathogenic
1700199	NM_001376.5(DYNC1H1):c.8234C>A (p.Thr2745Lys)	Pathogenic
1701046	NM_001376.5(DYNC1H1):c.6074G>A (p.Arg2025Gln)	Pathogenic
2000607	NM_001376.5(DYNC1H1):c.3269G>A (p.Arg1090Lys)	Pathogenic
2027827	NM_001376.5(DYNC1H1):c.3185A>C (p.Asp1062Ala)	Pathogenic
2066078	NM_001376.5(DYNC1H1):c.3371A>G (p.His1124Arg)	Pathogenic
208747	NM_001376.5(DYNC1H1):c.10033G>A (p.Glu3345Lys)	Pathogenic
224130	NM_001376.5(DYNC1H1):c.10573C>T (p.Arg3525Cys)	Pathogenic
2429633	NM_001376.5(DYNC1H1):c.6272G>A (p.Arg2091Gln)	Pathogenic
245597	NM_001376.5(DYNC1H1):c.5884C>T (p.Arg1962Cys)	Pathogenic
246081	NM_001376.5(DYNC1H1):c.1793G>T (p.Arg598Leu)	Pathogenic
246228	NM_001376.5(DYNC1H1):c.3370C>T (p.His1124Tyr)	Pathogenic
2506791	NM_001376.5(DYNC1H1):c.6058C>T (p.Pro2020Ser)	Pathogenic
2579938	NM_001376.5(DYNC1H1):c.4867C>T (p.Arg1623Trp)	Pathogenic
2743787	NM_001376.5(DYNC1H1):c.9466C>T (p.Gln3156Ter)	Pathogenic
3018108	NM_001376.5(DYNC1H1):c.1705C>T (p.Arg569Trp)	Pathogenic
3358996	NM_001376.5(DYNC1H1):c.10975dup (p.Arg3659fs)	Pathogenic
3636170	NM_001376.5(DYNC1H1):c.9928A>G (p.Met3310Val)	Pathogenic
3724841	NM_001376.5(DYNC1H1):c.12684+5G>T	Pathogenic
372934	NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu)	Pathogenic
449962	NM_001376.5(DYNC1H1):c.3278T>C (p.Phe1093Ser)	Pathogenic
453004	NM_001376.5(DYNC1H1):c.10348G>A (p.Glu3450Lys)	Pathogenic
4718392	NM_001376.5(DYNC1H1):c.3016-11T>A	Pathogenic
55854	NM_001376.5(DYNC1H1):c.10151G>A (p.Arg3384Gln)	Pathogenic
55855	NM_001376.5(DYNC1H1):c.10031G>A (p.Arg3344Gln)	Pathogenic

SpliceAI

9606 predictions. Top by Δscore:

Variant	Effect	Δscore
14:101975702:T:G	acceptor_gain	1.0000
14:101975702:T:TA	acceptor_gain	1.0000
14:101975709:TA:T	acceptor_loss	1.0000
14:101975710:A:AC	acceptor_loss	1.0000
14:101975710:A:AG	acceptor_gain	1.0000
14:101975710:AGAG:A	acceptor_gain	1.0000
14:101975711:G:GA	acceptor_gain	1.0000
14:101975711:GA:G	acceptor_gain	1.0000
14:101975711:GAGG:G	acceptor_gain	1.0000
14:101975711:GAGGA:G	acceptor_gain	1.0000
14:101975796:ATAG:A	donor_gain	1.0000
14:101975797:TAG:T	donor_gain	1.0000
14:101975799:GGTG:G	donor_loss	1.0000
14:101975801:T:A	donor_loss	1.0000
14:101979314:TTTA:T	acceptor_loss	1.0000
14:101979315:TTAG:T	acceptor_loss	1.0000
14:101979316:TA:T	acceptor_loss	1.0000
14:101979317:A:AG	acceptor_gain	1.0000
14:101979317:AGCT:A	acceptor_loss	1.0000
14:101979317:AGCTT:A	acceptor_gain	1.0000
14:101979318:G:GT	acceptor_gain	1.0000
14:101979318:GC:G	acceptor_gain	1.0000
14:101979318:GCT:G	acceptor_gain	1.0000
14:101979318:GCTT:G	acceptor_gain	1.0000
14:101979318:GCTTG:G	acceptor_gain	1.0000
14:101979489:ACAG:A	donor_loss	1.0000
14:101979490:CAG:C	donor_loss	1.0000
14:101979491:AG:A	donor_loss	1.0000
14:101979492:GG:G	donor_loss	1.0000
14:101979493:GT:G	donor_loss	1.0000

AlphaMissense

30703 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:101979745:T:A	V182D	1.000
14:101979766:T:C	L189P	1.000
14:101979778:T:A	L193H	1.000
14:101979778:T:C	L193P	1.000
14:101979781:T:C	L194P	1.000
14:101979790:A:C	Q197P	1.000
14:101979805:T:C	I202T	1.000
14:101979805:T:G	I202S	1.000
14:101979954:T:A	W252R	1.000
14:101979954:T:C	W252R	1.000
14:101980374:T:C	L262P	1.000
14:101980401:C:A	A271D	1.000
14:101980409:G:A	E274K	1.000
14:101980410:A:T	E274V	1.000
14:101980418:T:C	F277L	1.000
14:101980419:T:C	F277S	1.000
14:101980420:T:A	F277L	1.000
14:101980420:T:G	F277L	1.000
14:101980421:T:A	W278R	1.000
14:101980421:T:C	W278R	1.000
14:101980423:G:C	W278C	1.000
14:101980423:G:T	W278C	1.000
14:101980425:T:C	L279P	1.000
14:101980491:T:C	L301P	1.000
14:101980500:T:C	L304S	1.000
14:101980500:T:G	L304W	1.000
14:101980514:C:A	R309S	1.000
14:101980515:G:C	R309P	1.000
14:101980517:T:C	F310L	1.000
14:101980518:T:G	F310C	1.000

dbSNP variants (sampled 300 via entrez): RS1000036911 (14:102039861 G>A), RS1000105696 (14:102023272 C>T), RS1000109977 (14:102040075 C>T), RS1000114969 (14:101987920 A>G), RS1000165972 (14:101988343 G>A,T), RS1000221653 (14:102032687 A>G,T), RS1000259146 (14:102043735 C>T), RS1000276904 (14:102025288 T>C), RS1000307101 (14:102045812 G>A), RS1000308004 (14:102025744 C>G,T), RS1000315929 (14:101991177 A>G), RS1000333763 (14:101974319 G>A), RS1000363098 (14:101993867 C>T), RS1000410596 (14:101990939 G>A), RS1000478969 (14:101974898 C>A)

Disease associations

OMIM: gene MIM:600112 | disease phenotypes: MIM:614228, MIM:614563, MIM:158600, MIM:118220, MIM:164400, MIM:613091, MIM:253300, MIM:607432, MIM:182960, MIM:600361, MIM:213000, MIM:160500, MIM:615937, MIM:217990, MIM:616716, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	Definitive	Autosomal dominant
intellectual disability, autosomal dominant 13	Definitive	Autosomal dominant
Charcot-Marie-Tooth disease axonal type 2O	Strong	Autosomal dominant
dyneinopathy	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete neuronopathy, distal hereditary motor	Definitive	AD

Mondo (38): Charcot-Marie-Tooth disease axonal type 2O (MONDO:0013644), intellectual disability, autosomal dominant 13 (MONDO:0013805), autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (MONDO:0008026), neurodevelopmental disorder (MONDO:0700092), congenital nervous system disorder (MONDO:0002320), amyotrophic lateral sclerosis (MONDO:0004976), Charcot-Marie-Tooth disease (MONDO:0015626), autosomal dominant cerebellar ataxia (MONDO:0020380), autosomal dominant childhood-onset proximal spinal muscular atrophy (MONDO:0018190), intellectual disability (MONDO:0001071), hereditary motor and sensory neuropathy (MONDO:0015358), autism spectrum disorder (MONDO:0005258), asphyxiating thoracic dystrophy 3 (MONDO:0013127), spinal muscular atrophy (MONDO:0001516), peripheral neuropathy (MONDO:0005244)

Orphanet (32): Autosomal dominant Charcot-Marie-Tooth disease type 2O (Orphanet:284232), DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy (Orphanet:209341), Autosomal dominant childhood-onset proximal spinal muscular atrophy (Orphanet:363447), Amyotrophic lateral sclerosis (Orphanet:803), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Autosomal dominant cerebellar ataxia (Orphanet:99), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome, Majewski type (Orphanet:93269), Short rib-polydactyly syndrome, Saldino-Noonan type (Orphanet:93270), Short rib-polydactyly syndrome, Verma-Naumoff type (Orphanet:93271), Lissencephaly (Orphanet:48471), Autosomal dominant distal hereditary motor neuropathy (Orphanet:140465), Hereditary motor and sensory neuropathy type 5 (Orphanet:64751), Polymicrogyria (Orphanet:35981), Isolated cerebellar agenesis (Orphanet:1398)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000297	Facial hypotonia
HP:0000494	Downslanted palpebral fissures
HP:0000750	Delayed speech and language development
HP:0001169	Broad palm
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001302	Pachygyria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001357	Plagiocephaly
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001769	Broad foot
HP:0001773	Short foot
HP:0001883	Talipes
HP:0002079	Hypoplasia of the corpus callosum
HP:0002359	Frequent falls
HP:0002365	Hypoplasia of the brainstem
HP:0002460	Distal muscle weakness
HP:0002510	Spastic tetraplegia
HP:0002515	Waddling gait
HP:0002936	Distal sensory impairment
HP:0003445	EMG: neuropathic changes
HP:0003474	Somatic sensory dysfunction

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007656_14	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	1.000000e-11

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D004830	Epilepsy, Tonic-Clonic	C10.228.140.490.375.290
D015417	Hereditary Sensory and Motor Neuropathy	C10.500.300; C10.574.500.495; C10.668.829.800.300; C16.131.666.300; C16.320.400.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054082	Lissencephaly	C10.500.507.450.499; C16.131.666.507.450.499
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009134	Muscular Atrophy, Spinal	C10.228.854.468; C10.574.562.500; C10.668.467.500
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500
D011115	Polyneuropathies	C10.668.829.800
C562568	Cerebellar Hypoplasia (supp.)
C537602	Short rib-polydactyly syndrome, Verma-Naumoff type (supp.)
C563560	Spinal Muscular Atrophy, Childhood, Proximal, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724913 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.89	Kd	1302	nM	CHEMBL3752910
5.89	ED50	1302	nM	CHEMBL3752910
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148270: Binding affinity to human DYNC1H1 incubated for 45 mins by Kinobead based pull down assay	kd	1.3015	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178758: Inhibition of DYNC1H1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases expression	4
bisphenol F	increases expression, affects cotreatment, decreases expression	2
methylmercuric chloride	increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
cobaltous chloride	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
Arsenic Trioxide	increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cisplatin	decreases expression, affects cotreatment	2
Cadmium Chloride	increases expression	2
beta-Naphthoflavone	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, affects oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	decreases expression, increases abundance	1
ochratoxin A	increases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	increases abundance, affects cotreatment, affects expression, affects oxidation	1
perfluorooctane sulfonic acid	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, affects reaction	1
2-palmitoylglycerol	increases expression	1
torcetrapib	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651312	Binding	Binding affinity to human DYNC1H1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3QZ	CRICKi004-A	Induced pluripotent stem cell	Female
CVCL_C3R0	CRICKi005-A	Induced pluripotent stem cell	Male
CVCL_C3R1	CRICKi006-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease