# NM_016156.6(MTMR2):c.1756C>A (p.Arg586=)

https://sugi.bio/variant/mtmr2-p-arg586

## Summary

**MTMR2 p.Arg586= (c.1756C>A)** is classified **Benign** in MTMR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 9.05%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

**At a glance:** Benign · review: Multiple submitters · rsID rs61735577 · 7 submitters · 3 linked conditions · common (popmax 9.05%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the MTMR2 gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to Charcot-Marie-Tooth disease.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 59 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006034/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MTMR2](https://sugi.bio/atlas/gene/MTMR2/) |
| Protein change (HGVS p.) | p.Arg586= |
| Coding change (HGVS c.) | c.1756C>A |
| MANE Select transcript | [NM_016156](https://www.ncbi.nlm.nih.gov/nuccore/NM_016156) |
| dbSNP | [rs61735577](https://www.ncbi.nlm.nih.gov/snp/rs61735577/) |
| Variant type | single nucleotide variant |
| Location | chr11:95836162-95836162 (GRCh38) |
| ClinVar | [VCV306536](https://www.ncbi.nlm.nih.gov/clinvar/variation/306536/) |

**All HGVS expressions:** `LRG_257:g.93046C>A`, `LRG_257t1:c.1756C>A`, `NC_000011.10:g.95836162G>T`, `NC_000011.9:g.95569326G>T`, `NG_008333.1:g.93046C>A`, `NM_001243571.2:c.1540C>A`, `NM_016156.6:c.1756C>A`, `NM_201278.3:c.1540C>A`, `NM_201281.3:c.1540C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 9.05%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 1.399, GERP -2.62, phastCons 0.866 — weakly conserved position
- CADD: **PHRED 5.317**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.30 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **9.05%** (sas) · FAF95 8.89% · FAF99 8.82% · 8,239/91,042 in the highest group · 44,523/1,612,476 alleles overall — common (popmax 9.05%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 9.05% | 11 |
| Finnish (not grpmax-eligible) | 7.68% | 13 |
| Middle Eastern | 6.66% | 15 |
| African / African-American | 5.69% | 18 |
| Remaining individuals (not grpmax-eligible) | 2.82% | 35 |
| European (non-Finnish) | 2.01% | 50 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.71% | 59 |
| Admixed American | 1.27% | 79 |
| East Asian | 0.058% | 1,725 |

*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}

**MTMR2** population constraint: LOEUF 0.9, pLI 1.1947e-11, missense-Z 1.6219. *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):

- **demyelinating hereditary motor and sensory neuropathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.44, 81% of residues very-high.

**5 experimental structure(s)** (PDB): [1LW3](https://www.rcsb.org/structure/1LW3), [1M7R](https://www.rcsb.org/structure/1M7R), [1ZSQ](https://www.rcsb.org/structure/1ZSQ), [1ZVR](https://www.rcsb.org/structure/1ZVR), [5GNH](https://www.rcsb.org/structure/5GNH).

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

*Describes the biological roles of MTMR2 (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:** MTMR2's established molecular role includes phosphatidylinositol-3-phosphate phosphatase activity.


### Pathways affected {#pathways}

MTMR2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PIPs at the ER membrane](https://reactome.org/content/detail/R-HSA-1483248) | curated |
| [Synthesis of PIPs at the late endosome membrane](https://reactome.org/content/detail/R-HSA-1660517) | curated |
| [Synthesis of PIPs at the early endosome membrane](https://reactome.org/content/detail/R-HSA-1660516) | electronic |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | electronic |

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

**Molecular function:** phosphatidylinositol-3-phosphate phosphatase activity, phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity.

**Biological process:** phosphatidylinositol dephosphorylation, regulation of phosphatidylinositol dephosphorylation.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (6 Benign, 1 benign).

**Submission history:** 7 submissions (2015–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Molecular Genetics Laboratory, London Health Sciences Centre | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2025-06-30 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-05-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/), [Charcot-Marie-Tooth disease type 4B1](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4b1/), [Charcot-Marie-Tooth disease type 4](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4B1, not provided, not specified, Charcot-Marie-Tooth Neuropathy, Charcot-Marie-Tooth Hereditary Neuropathy, Charcot-Marie-Tooth disease, type IV, Charcot-Marie-Tooth, Type 4, AllHighlyPenetrant.

## Similar variants {#similar}

Related MTMR2 variant pages (same residue, condition, or type): [MTMR2 p.Arg586Gln](/variant/mtmr2-p-arg586gln), [MTMR2 p.Arg586Gly](/variant/mtmr2-p-arg586gly), [MTMR2 p.Arg586Trp](/variant/mtmr2-p-arg586trp), [MTMR2 c.804+2T>G](/variant/mtmr2-c-804-plus-2t-g), [MTMR2 p.Arg102Ter](/variant/mtmr2-p-arg102ter), [MTMR2 p.Arg162Ter](/variant/mtmr2-p-arg162ter), [MTMR2 p.Arg364Ter](/variant/mtmr2-p-arg364ter), [MTMR2 p.Gln590Ter](/variant/mtmr2-p-gln590ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 306536). 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.*