MORC2

Chr 22AD

MORC family CW-type zinc finger 2

Also known as: CMT2Z, DIGFAN, ZCW3, ZCWCC1

NCBI Gene: 22880 ENSG00000133422 UniProt: Q9Y6X9 OMIM: 616661

This gene encodes an ATP-dependent chromatin remodeler that regulates heterochromatin condensation, epigenetic gene silencing, and DNA damage response, with additional cytosolic functions in lipid metabolism. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2Z (axonal neuropathy) and a neurodevelopmental disorder characterized by developmental delay, impaired growth, dysmorphic features, and axonal neuropathy. The gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.21), indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.202 OMIM phenotypes

Clinical Summary— MORC2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 234 VUS of 480 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.20LOEUF

pLI 1.000

Z-score 6.31

OE 0.10 (0.06–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.23Z-score

OE missense 0.63 (0.58–0.69)

376 obs / 597.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.10 (0.06–0.20)

0≤0.351.4

Missense OE0.63 (0.58–0.69)

0≤0.61.4

Synonymous OE0.92

0≤1.21.6

LoF obs/exp: 6 / 57.8Missense obs/exp: 376 / 597.9Syn Z: 0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMORC2-related axonal neuropathy and neurodevelopmental disorderOTHERAD

0.2798th %ile

GOF

0.2995th %ile

LOF

0.70top 10%

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

LOFprediction above median · LOEUF 0.20

GOF1 literature citation

Literature Evidence

GOFConsistent with the genetic data which suggests a gain-of-function mechanism underlying the pathogenicity of the mutations, MORC2 harboring the R252W mutation did encode a functional protein capable of restoring HUSH-mediated transgene repression in MORC2 knockout HeLa cellsPMID:28581500

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.