MYH3

Chr 17ADAR

myosin heavy chain 3

NCBI Gene: 4621ENSG00000109063UniProt: P11055

Muscle contraction

Primary Disease Associations & Inheritance

Arthrogryposis, distal, type 2A (Freeman-Sheldon)MIM #193700
AD
Arthrogryposis, distal, type 2B3 (Sheldon-Hall)MIM #618436
AD
Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1AMIM #178110
AD
Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1BMIM #618469
AR
584
ClinVar variants
31
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MYH3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 356 VUS of 584 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.63LOEUF
pLI 0.000
Z-score 4.70
OE 0.50 (0.40–0.63)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.74Z-score
OE missense 0.85 (0.80–0.90)
855 obs / 1011.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.50 (0.40–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.80–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 51 / 102.2Missense obs/exp: 855 / 1011.1Syn Z: -0.97

ClinVar Variant Classifications

584 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic12
VUS356
Likely Benign195
Benign2
19
Pathogenic
12
Likely Pathogenic
356
VUS
195
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
13
0
19
Likely Pathogenic
7
5
0
0
12
VUS
3
314
34
5
356
Likely Benign
0
3
83
109
195
Benign
0
0
2
0
2
Total16322132114584

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

View in ClinVar →

Protein Context — Lollipop Plot

MYH3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MYH3-related spondylocarpotarsal synostosis syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

MYH3-related distal arthrogryposis

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Arthrogryposis, distal, type 2A (Freeman-Sheldon)

MIM #193700

Molecular basis of disorder known

Autosomal dominant

Arthrogryposis, distal, type 2B3 (Sheldon-Hall)

MIM #618436

Molecular basis of disorder known

Autosomal dominant

Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A

MIM #178110

Molecular basis of disorder known

Autosomal dominant

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B

MIM #618469

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases.
Qin Y et al.·BMC Med Genomics
2023Cohort
Sheldon-Hall syndrome.
Toydemir RM et al.·Orphanet J Rare Dis
2009Review
Hereditary myosin myopathies.
Oldfors A·Neuromuscul Disord
2007Review
A novel pathogenic MYH3 mutation in a child with Sheldon-Hall syndrome and vertebral fusions.
Scala M et al.·Am J Med Genet A
2018Review
Thick filament diseases.
Oldfors A et al.·Adv Exp Med Biol
2008Review
Functional Insights in PLS3-Mediated Osteogenic Regulation.
Zhong W et al.·Cells
2024Functional
Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
Morali B et al.·Clin Genet
2024Case report
Myosinopathies: pathology and mechanisms.
Tajsharghi H et al.·Acta Neuropathol
2013Review
Homozygous Pathogenic MYH3 Variants Associated With Arthrogryposis and Lingual Dystonia.
Mouraux C et al.·Tremor Other Hyperkinet Mov (N Y)
2025Case report
Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum.
Pérez-Vidarte F et al.·Ann Clin Transl Neurol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools