# NM_001303256.3(MORC2):c.2193G>A (p.Pro731=)

https://sugi.bio/variant/morc2-p-pro731

## Summary

**MORC2 p.Pro731= (c.2193G>A)** is classified **Uncertain significance** in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-17). Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2Z.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1049816749 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the MORC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease axonal type 2Z.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Diagnostic panels | MORC2 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Autosomal dominant Charcot-Marie-Tooth disease type 2Z** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Reduced tendon reflexes — Very frequent (99-80%)
- Distal muscle weakness — Very frequent (99-80%)
- Sensory axonal neuropathy — Very frequent (99-80%)
- Lower limb amyotrophy — Very frequent (99-80%)
- Mixed demyelinating and axonal polyneuropathy — Very frequent (99-80%)
- Distal lower limb amyotrophy — Very frequent (99-80%)
- Distal lower limb muscle weakness — Very frequent (99-80%)
- Abnormality of peripheral somatosensory evoked potentials — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017829/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MORC2](https://sugi.bio/atlas/gene/MORC2/) |
| Protein change (HGVS p.) | p.Pro731= |
| Coding change (HGVS c.) | c.2193G>A |
| MANE Select transcript | [NM_001303256](https://www.ncbi.nlm.nih.gov/nuccore/NM_001303256) |
| dbSNP | [rs1049816749](https://www.ncbi.nlm.nih.gov/snp/rs1049816749/) |
| Variant type | single nucleotide variant |
| Location | chr22:30934781-30934781 (GRCh38) |
| ClinVar | [VCV2149740](https://www.ncbi.nlm.nih.gov/clinvar/variation/2149740/) |

**All HGVS expressions:** `NC_000022.10:g.31330768C>T`, `NC_000022.11:g.30934781C>T`, `NG_046752.1:g.38717G>A`, `NM_001303256.3:c.2193G>A`, `NM_001303257.2:c.2193G>A`, `NM_014941.3:c.2007G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.271, GERP -2.89, phastCons 0.044 — weakly conserved position
- CADD: **PHRED 16.57**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.01**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.01**, donor gain **0.02**.
- Pangolin: Δ**0.60** (loss), gain 0.01 / loss 0.60. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,888 in the highest group · 7/1,613,698 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,888 |
| Admixed American | 0.00167% | 59,992 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,014 |
| European (non-Finnish) | 0.000254% | 393,272 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MORC2** population constraint: LOEUF 0.3, pLI 1, missense-Z 4.4514. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Leigh syndrome** — Limited (AD)
- **Charcot-Marie-Tooth disease axonal type 2Z** — Definitive (AD)

## Protein context {#protein}

Residue **731** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 78.37, 52% of residues very-high.

**9 experimental structure(s)** (PDB): [5OF9](https://www.rcsb.org/structure/5OF9), [5OFA](https://www.rcsb.org/structure/5OFA), [5OFB](https://www.rcsb.org/structure/5OFB), [9CDF](https://www.rcsb.org/structure/9CDF), [9CDG](https://www.rcsb.org/structure/9CDG), [9CDH](https://www.rcsb.org/structure/9CDH) — incl. mutant structure 9CDF.

## What this gene does {#gene-function}

*Describes the biological roles of MORC2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MORC2's established molecular role includes magnesium ion binding. p.Pro731= falls in the disordered region.


### Pathways affected {#pathways}

MORC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Fatty acyl-CoA biosynthesis](https://reactome.org/content/detail/R-HSA-75105) | curated |
| [Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex](https://reactome.org/content/detail/R-HSA-9843970) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** magnesium ion binding, chromatin binding, ATP binding, zinc ion binding, ATP hydrolysis activity, protein homodimerization activity.

**Biological process:** chromatin remodeling, DNA damage response, constitutive heterochromatin formation, transposable element silencing by heterochromatin formation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-17.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-17 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease axonal type 2Z](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2z/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease axonal type 2Z, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2Z, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2Z.

## Similar variants {#similar}

Related MORC2 variant pages (same residue, condition, or type): [MORC2 p.Pro731Leu](/variant/morc2-p-pro731leu), [MORC2 p.Arg132Cys](/variant/morc2-p-arg132cys), [MORC2 p.Arg252Trp](/variant/morc2-p-arg252trp), [MORC2 p.Arg266Ser](/variant/morc2-p-arg266ser), [MORC2 p.Asp466Asn](/variant/morc2-p-asp466asn), [MORC2 p.Glu236Gly](/variant/morc2-p-glu236gly), [MORC2 p.Glu27Lys](/variant/morc2-p-glu27lys), [MORC2 p.Ser87Leu](/variant/morc2-p-ser87leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2149740). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*