Nebulin is a giant cytoskeletal protein that comprises 3-4% of myofibrillar protein in skeletal muscle sarcomeres and regulates thin filament length and muscle contraction. Mutations cause autosomal recessive nemaline myopathy and arthrogryposis multiplex congenita through a predicted gain-of-function mechanism. The protein undergoes extensive alternative splicing with tissue- and developmental stage-specific isoforms ranging from 600-800 kD.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 0.422 OMIM phenotypes
VCEP Guidelines: Congenital MyopathiesReleased
ClinGen Panel
Clinical SummaryNEB
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Gene-Disease Validity (ClinGen)
nemaline myopathy 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.42LOEUF
pLI 0.000
Z-score 11.58
OE 0.37 (0.320.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.04Z-score
OE missense 1.00 (0.971.03)
3782 obs / 3774.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.37 (0.320.42)
00.351.4
Missense OE1.00 (0.971.03)
00.61.4
Synonymous OE1.01
01.21.6
LoF obs/exp: 145 / 392.5Missense obs/exp: 3782 / 3774.9Syn Z: -0.36
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveNEB-related typical nemaline myopathyLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6356th %ile
GOF
0.7028th %ile
LOF
0.2190th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

NEB · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗