MYH4

Chr 17

myosin heavy chain 4

Also known as: MYH2B, MyHC-2B, MyHC-IIb

NCBI Gene: 4622 ENSG00000264424 UniProt: Q9Y623 OMIM: 160742

The protein is a myosin heavy chain that enables muscle contraction within myofibrils. Mutations cause autosomal dominant myopathy with early-onset muscle weakness and contractures, as well as autosomal recessive developmental and epileptic encephalopathy with microcephaly. The gene shows very low constraint against loss-of-function variants, suggesting tolerance to such mutations in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Enables double-stranded RNA binding activity. Involved in muscle contraction. Located in myofibril. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.04

Clinical Summary— MYH4

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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

292 VUS of 311 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?

1.04LOEUF

pLI 0.000

Z-score 1.18

OE 0.88 (0.74–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.11Z-score

OE missense 0.99 (0.94–1.04)

1020 obs / 1030.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.74–1.04)

0≤0.351.4

Missense OE?0.99 (0.94–1.04)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 92 / 105.1Missense obs/exp: 1020 / 1030.0Syn Z: 0.02

This gene — mechanism propensity

0.82top 10%

GOF

0.6248th %ile

LOF

0.3357th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.

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

ClinVar Variant Classifications

311 submitted variants in ClinVar

ClinVar

Classification Summary

VUS292

Likely Benign7

Benign8

Conflicting1

292

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	291	0	0	292
Likely Benign	0	5	0	2	7
Benign	0	5	0	3	8
Conflicting	—				1
Total	1	301	0	5	308

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap MYH4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →