MYH2

Chr 17ADAR

myosin heavy chain 2

Also known as: CMYO6, CMYP6, IBM3, MYH2A, MYHSA2, MYHas8, MyHC-2A, MyHC-IIa

NCBI Gene: 4620 ENSG00000125414 UniProt: Q9UKX2 OMIM: 160740

The MYH2 gene encodes a class II myosin heavy chain that functions as an actin-based motor protein essential for skeletal muscle contraction. Mutations cause congenital myopathy 6 with ophthalmoplegia through a dominant-negative mechanism, inherited in both autosomal dominant and autosomal recessive patterns. The protein localizes to myofibrils in the cytoplasm and is part of heterohexameric muscle myosin complexes that generate mechanical force for muscle function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.691 OMIM phenotype

Clinical Summary— MYH2

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Gene-Disease Validity (ClinGen)

myopathy, proximal, and ophthalmoplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

124 unique Pathogenic / Likely Pathogenic· 977 VUS of 1731 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 →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 4.15

OE 0.55 (0.44–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.97Z-score

OE missense 0.82 (0.78–0.87)

826 obs / 1001.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.44–0.69)

0≤0.351.4

Missense OE?0.82 (0.78–0.87)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 53 / 97.1Missense obs/exp: 826 / 1001.7Syn Z: -0.69

This gene — mechanism propensity

0.89top 5%

GOF

0.7127th %ile

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNBecause it is known that the expression of MyHC IIa increases with age this observation explains the progressive course of the disease in adulthood and confirms the dominant negative effect of the p.E706K mutation.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23489661 ↗

ClinVar Variant Classifications

1731 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68

Likely Pathogenic56

VUS977

Likely Benign512

Benign63

Conflicting52

Pathogenic

Likely Pathogenic

977

VUS

512

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	3	2	0	68
Likely Pathogenic	52	2	2	0	56
VUS	6	881	69	21	977
Likely Benign	0	10	188	314	512
Benign	0	1	53	9	63
Conflicting	—				52
Total	121	897	314	344	1,728

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap MYH2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →