DYNC1H1

Chr 14AD

dynein cytoplasmic 1 heavy chain 1

Also known as: CDCBM13, CMT2O, DHC1, DHC1a, DNCH1, DNCL, DNECL, DYHC

NCBI Gene: 1778ENSG00000197102UniProt: Q14204OMIM: 600112

This protein functions as a cytoplasmic dynein heavy chain that serves as a microtubule-activated ATPase molecular motor essential for retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Autosomal dominant mutations cause Charcot-Marie-Tooth disease type 2O, complex cortical dysplasia with brain malformations, and lower extremity-predominant spinal muscular atrophy. The gene is highly intolerant to loss-of-function variants, indicating pathogenicity likely results from haploinsufficiency or dominant-negative effects disrupting cytoplasmic dynein function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.083 OMIM phenotypes
Clinical Summary— DYNC1H1
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Gene-Disease Validity (ClinGen)
obsolete neuronopathy, distal hereditary motor · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
21 unique Pathogenic / Likely Pathogenic· 229 VUS of 500 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — DYNC1H1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.08LOEUF
pLI 1.000
Z-score 13.32
OE 0.05 (0.03–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
10.97Z-score
OE missense 0.39 (0.37–0.41)
1022 obs / 2593.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.05 (0.03–0.08)
0≤0.351.4
Missense OE0.39 (0.37–0.41)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 11 / 228.0Missense obs/exp: 1022 / 2593.9Syn Z: -1.72
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveDYNC1H1-related severe intellectual disability with neuronal migration disorderOTHERAD
definitiveDYNC1H1-related spinal muscular atrophy, lower extremity-predominantOTHERAD
DN
0.3594th %ile
GOF
0.4579th %ile
LOF
0.57top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · LOEUF 0.08

Literature Evidence

LOFWillemsen et al. (2012) noted that DYNC1H1 interacts with LIS1 (601545), haploinsufficiency of which results in the severe neuronal migration disorder lissencephaly-1 (607432), and that Dync1h1 mutant mice show neuronal migration defects (Ori-McKenney and Vallee, 2011), providing evidence of the patPMID:22368300

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic18
VUS229
Likely Benign185
Benign2
Conflicting4
3
Pathogenic
18
Likely Pathogenic
229
VUS
185
Likely Benign
2
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
3
0
3
Likely Pathogenic
3
15
0
0
18
VUS
14
203
10
2
229
Likely Benign
0
17
67
101
185
Benign
0
0
2
0
2
Conflicting
—4
Total1723582103441

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DYNC1H1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Generation of iPSC line NIMHi033-A from an Indian patient with Autism Spectrum Disorder carrying mutation in DYNC1H1 gene.
Niranjana Murthy AS et al.·Stem Cell Res
2026
DYNC1H1 in Spinal Muscular Atrophy: Diagnostic Findings From Two Families and a Comprehensive Review of Its Role in Neuromuscular and Neurodevelopmental Disorders.
Namdari M et al.·Mol Genet Genomic Med
2025Open AccessReview
KLF1 Promotes Non-Small Cell Lung Cancer Cell Proliferation and Invasion by Upregulating the LINC02159/DYNC1H1 Pathway.
Yang H.·Kaohsiung J Med Sci
2025Open Access
Altered Metabolism in Heterozygous Mice With a Mutation in the Motor Domain of Cytoplasmic Dynein, DYNC1H1 (AAA4; c9052C>T(P3018S)).
Sidoli S et al.·Proteomics
2025
A novel mutation in the DYNC1H1 gene causing developmental and epileptic encephalopathy treated with ketogenic diet: A case report.
Zhao F et al.·Medicine (Baltimore)
2025Open AccessCase report
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients