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

This gene encodes a member of the Microrchidia (MORC) protein superfamily. The encoded protein is known to regulate the condensation of heterochromatin in response to DNA damage and play a role in repressing transcription. The protein has been found to regulate the activity of ATP citrate lyase via specific interaction with this enzyme in the cytosol of lipogenic breast cancer cells. The protein also plays a role in lipogenesis and adipocyte differentiation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

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

35 unique Pathogenic / Likely Pathogenic· 534 VUS of 1063 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

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 OE?0.10 (0.06–0.20)

0≤0.351.4

Missense OE?0.63 (0.58–0.69)

0≤0.61.4

Synonymous OE?0.92

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 disorder (DIGFAN syndrome)OTHERAD

This gene — mechanism propensity

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 · 100% of P/LP are missense

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 cells1

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

References

1.PMID 28581500 ↗

ClinVar Variant Classifications

1063 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic25

VUS534

Likely Benign406

Benign41

Conflicting28

Pathogenic

Likely Pathogenic

534

VUS

406

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	10	0	0	10
Likely Pathogenic	0	25	0	0	25
VUS	36	440	45	13	534
Likely Benign	0	14	195	197	406
Benign	0	0	32	9	41
Conflicting	—				28
Total	36	489	272	219	1,044

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap MORC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →