# NM_000254.3(MTR):c.1092G>A (p.Arg364=)

https://sugi.bio/variant/mtr-p-arg364

## Summary

**MTR p.Arg364= (c.1092G>A)** is classified **Likely benign** in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-27). Very rare (popmax 0.000932%, nfe); Associated with methylcobalamin deficiency type cblG.

**At a glance:** Likely benign · review: Single submitter · rsID rs1326750147 · 1 submitter · 1 linked condition · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the MTR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to methylcobalamin deficiency type cblG.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | MTR is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Homocystinuria without methylmalonic aciduria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Very frequent (99-80%)
- Megaloblastic bone marrow — Very frequent (99-80%)
- Nystagmus — Frequent (79-30%)
- Psychosis — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Cerebral cortical atrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003577/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MTR](https://sugi.bio/atlas/gene/MTR/) |
| Protein change (HGVS p.) | p.Arg364= |
| Coding change (HGVS c.) | c.1092G>A |
| MANE Select transcript | [NM_000254](https://www.ncbi.nlm.nih.gov/nuccore/NM_000254) |
| dbSNP | [rs1326750147](https://www.ncbi.nlm.nih.gov/snp/rs1326750147/) |
| Variant type | single nucleotide variant |
| Location | chr1:236831982-236831982 (GRCh38) |
| ClinVar | [VCV2992977](https://www.ncbi.nlm.nih.gov/clinvar/variation/2992977/) |

**All HGVS expressions:** `NC_000001.10:g.236995282G>A`, `NC_000001.11:g.236831982G>A`, `NG_008959.1:g.41702G>A`, `NM_000254.3:c.1092G>A`, `NM_001291939.1:c.1092G>A`, `NM_001291940.2:c.-34+2714G>A`, `NM_001410942.1:c.1092G>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 (below), not from a missing predictor score.
- Conservation: phyloP 5.702, GERP 1.78, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.819**. 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>T, Δ0.21 acceptor 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,960 in the highest group · 11/1,613,966 alleles overall — very rare (popmax 0.000932%, 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}

**MTR** population constraint: LOEUF 0.625, pLI 2.5517e-09, missense-Z 3.3131; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **methylcobalamin deficiency type cblG** — Definitive (AR)

## Protein context {#protein}

Residue **364** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 87.60, 55% of residues very-high.

**9 experimental structure(s)** (PDB): [2O2K](https://www.rcsb.org/structure/2O2K), [4CCZ](https://www.rcsb.org/structure/4CCZ), [9SSP](https://www.rcsb.org/structure/9SSP), [9SSQ](https://www.rcsb.org/structure/9SSQ), [9SSR](https://www.rcsb.org/structure/9SSR), [9SSS](https://www.rcsb.org/structure/9SSS) — incl. mutant structure 2O2K.

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

*Describes the biological roles of MTR (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:** MTR's established molecular role includes methionine synthase activity. In Reactome, MTR is annotated in disease pathway(s) including **Defective MTR causes HMAG**, **Defective MTRR causes HMAE**.

**Disease mechanism (Reactome):** MTR loss or alteration is curated in [Defective MTR causes HMAG](https://reactome.org/content/detail/R-HSA-3359469), [Defective MTRR causes HMAE](https://reactome.org/content/detail/R-HSA-3359467).

### Pathways affected {#pathways}

MTR participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective MTR causes HMAG](https://reactome.org/content/detail/R-HSA-3359469) | curated |
| ⚕ [Defective MTRR causes HMAE](https://reactome.org/content/detail/R-HSA-3359467) | curated |
| [Cobalamin (Cbl) metabolism](https://reactome.org/content/detail/R-HSA-9759218) | curated |
| [Methylation](https://reactome.org/content/detail/R-HSA-156581) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [Sulfur amino acid metabolism](https://reactome.org/content/detail/R-HSA-1614635) | curated |

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

**Molecular function:** methionine synthase activity.

**Biological process:** obsolete methionine biosynthetic process, cobalamin metabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-27 |

## Associated conditions {#conditions}

[methylcobalamin deficiency type cblG](https://sugi.bio/atlas/disease/methylcobalamin-deficiency-type-cblg/).

**Reported phenotype names (ClinVar):** Methylcobalamin deficiency type cblG, Functional methionine synthase deficiency type cblG, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE.

## Similar variants {#similar}

Related MTR variant pages (same residue, condition, or type): [MTR c.1812+1G>A](/variant/mtr-c-1812-plus-1g-a), [MTR c.2474-1G>C](/variant/mtr-c-2474-minus-1g-c), [MTR c.2595-2A>G](/variant/mtr-c-2595-minus-2a-g), [MTR c.340-166A>G](/variant/mtr-c-340-minus-166a-g), [MTR c.609+1088G>A](/variant/mtr-c-609-plus-1088g-a), [MTR c.866-2A>C](/variant/mtr-c-866-minus-2a-c), [MTR p.Arg1147Ter](/variant/mtr-p-arg1147ter), [MTR p.Arg585Ter](/variant/mtr-p-arg585ter).

### 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 2992977). 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.*