DYNC2H1

Chr 11ARDigenic recessive

dynein cytoplasmic 2 heavy chain 1

Also known as: ATD3, DHC1b, DHC2, DNCH2, DYH1B, SRPS2B, SRTD3, hdhc11

NCBI Gene: 79659 ENSG00000187240 UniProt: Q8NCM8 OMIM: 603297

This gene encodes a cytoplasmic dynein protein that functions as a motor for retrograde intraflagellar transport and is essential for cilia biogenesis. Mutations cause a spectrum of ciliopathies characterized by polydactyly, abnormal skeletal development, and polycystic kidneys, with autosomal recessive inheritance. The gene shows high constraint against loss-of-function variants, reflecting its critical role in cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Short-rib thoracic dysplasia 3 with or without polydactylyMIM #613091

ARDigenic recessive

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · asphyxiating thoracic dystrophy 3 · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.58

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — DYNC2H1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 7.11

OE 0.49 (0.42–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.91Z-score

OE missense 0.94 (0.91–0.98)

1890 obs / 2004.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.42–0.58)

0≤0.351.4

Missense OE?0.94 (0.91–0.98)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 113 / 229.3Missense obs/exp: 1890 / 2004.6Syn Z: -0.73

Background carrier burden — how many people carry a rare variant somewhere in DYNC2H1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 12

5,254 rare PASS variants

Rare truncating (LoF)

1 in 220

828 rare PASS variants

Rare synonymous (reference)

1 in 27

1,807 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DYNC2H1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 17	1 in 240
South Asian	~43k	1 in 12	1 in 180
Remaining (unassigned)	~30k	1 in 11	1 in 170
European (Finnish)	~27k	1 in 42	1 in 950
Admixed American	~22k	1 in 11	1 in 190
African / African American	~21k	1 in 11	1 in 130
East Asian	~20k	1 in 13	1 in 160
Ashkenazi Jewish	~13k	1 in 38	1 in 710
Middle Eastern	~2,884	1 in 13	1 in 280

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 59 of 89 coding exons well covered in gnomAD exomes; exons 2, 4, 9, 11, 13 and 25 more marginal. Genomes: all 89.? see exons ↓