# NM_000252.3(MTM1):c.1262G>A (p.Arg421Gln)

https://sugi.bio/variant/mtm1-p-arg421gln

## Summary

**MTM1 p.Arg421Gln (c.1262G>A)** is classified **Pathogenic/Likely pathogenic** in MTM1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.9896); Very rare (popmax 0.000112%, nfe); Associated with MTM1-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs587783772 · 9 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the MTM1 gene that is considered likely disease-causing, submitted by 9 submitters, and is linked to MTM1-related disorder.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MTM1](https://sugi.bio/atlas/gene/MTM1/) |
| Protein change (HGVS p.) | p.Arg421Gln |
| Coding change (HGVS c.) | c.1262G>A |
| MANE Select transcript | [NM_000252](https://www.ncbi.nlm.nih.gov/nuccore/NM_000252) |
| dbSNP | [rs587783772](https://www.ncbi.nlm.nih.gov/snp/rs587783772/) |
| Variant type | single nucleotide variant |
| Location | chrX:150659665-150659665 (GRCh38) |
| ClinVar | [VCV158914](https://www.ncbi.nlm.nih.gov/clinvar/variation/158914/) |

**All HGVS expressions:** `LRG_839:g.96092G>A`, `LRG_839t1:c.1262G>A`, `NC_000023.10:g.149828138G>A`, `NC_000023.11:g.150659665G>A`, `NG_008199.1:g.96092G>A`, `NM_000252.3:c.1262G>A`, `NM_001376906.1:c.1262G>A`, `NM_001376907.1:c.1151G>A`, `NM_001376908.1:c.1262G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9896) — concordant with the pathogenic call
- REVEL 0.974 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.34 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.781, GERP 2.24, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.55** across the covering region of the MANE Select transcript (150,657,963–150,663,592), spanning 5,629 bp. Chi-square p 2.6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/890,320 in the highest group · 1/1,205,805 alleles overall — very rare (popmax 0.000112%, nfe).

*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}

**MTM1** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **X-linked myotubular myopathy** — Definitive (XL)

## Protein context {#protein}

Residue **421** lies in the myotubularin phosphatase domain; a binding site; a UniProt-annotated variant site (in cnmx; severe; reduced activity and response to pi5p; does not affect interaction with des or mtmr12); a UniProt-annotated variant site (in cnmx; severe).

AlphaFold model confidence (whole protein): pLDDT 90.10, 80% of residues very-high.

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

*Describes the biological roles of MTM1 (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:** MTM1's established molecular role includes phosphatidylinositol-3-phosphate phosphatase activity. p.Arg421Gln falls in the myotubularin phosphatase domain.


### Pathways affected {#pathways}

MTM1 participates in **3 Reactome pathways** (⚕ = disease pathway):

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

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

**Molecular function:** phosphatidylinositol-3-phosphate phosphatase activity, phosphoprotein phosphatase activity, intermediate filament binding, phosphatidylinositol binding, phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity.

**Biological process:** protein dephosphorylation, mitochondrion organization, endosome to lysosome transport, regulation of vacuole organization, intermediate filament organization, phosphatidylinositol dephosphorylation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-17.

**Submitter consensus:** conflicting (9 Pathogenic, 1 Likely pathogenic).

**Submission history:** 10 submissions (2013–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-15 |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2013-02-08 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-12-31 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-22 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2021-02-01 |
| Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Pathogenic | criteria provided, single submitter | research | 2024-03-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-15 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-06-14 |

## Associated conditions {#conditions}

[MTM1-related disorder](https://sugi.bio/atlas/disease/mtm1-related-disorder/), [congenital fiber-type disproportion myopathy](https://sugi.bio/atlas/disease/congenital-fiber-type-disproportion-myopathy/), [X-linked myotubular myopathy](https://sugi.bio/atlas/disease/x-linked-myotubular-myopathy/), [centronuclear myopathy](https://sugi.bio/atlas/disease/centronuclear-myopathy/).

**Reported phenotype names (ClinVar):** MTM1-related disorder, Severe X-linked myotubular myopathy, not provided, Centronuclear myopathy, Congenital myopathy with fiber type disproportion, Inborn genetic diseases, MTM1-related condition, none provided, Myotubular myopathy, Centronuclear myopathy, congenital.

## Same-residue context {#hotspot}

Residue **421** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MTM1 p.Arg421Ter](/variant/mtm1-p-arg421ter), [MTM1 p.Arg421Leu](/variant/mtm1-p-arg421leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MTM1 variant pages (same residue, condition, or type): [MTM1 p.Arg421Ter](/variant/mtm1-p-arg421ter), [MTM1 p.Arg421Leu](/variant/mtm1-p-arg421leu), [MTM1 c.1644+1G>A](/variant/mtm1-c-1644-plus-1g-a), [MTM1 p.Arg224Ter](/variant/mtm1-p-arg224ter), [MTM1 p.Arg69Cys](/variant/mtm1-p-arg69cys), [MTM1 p.Gln451=](/variant/mtm1-p-gln451), [MTM1 p.Glu404Lys](/variant/mtm1-p-glu404lys), [MTM1 p.Pro205Leu](/variant/mtm1-p-pro205leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 158914). 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.*