# NM_000254.3(MTR):c.901C>G (p.Pro301Ala)

https://sugi.bio/variant/mtr-p-pro301ala

## Summary

**MTR p.Pro301Ala (c.901C>G)** is classified **Uncertain significance** in MTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-12). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00695%, nfe); Associated with methylcobalamin deficiency type cblG.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs766371534 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00695%, nfe)

## For patients & families {#patients}

This is a change in the MTR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Pro301Ala |
| Coding change (HGVS c.) | c.901C>G |
| MANE Select transcript | [NM_000254](https://www.ncbi.nlm.nih.gov/nuccore/NM_000254) |
| dbSNP | [rs766371534](https://www.ncbi.nlm.nih.gov/snp/rs766371534/) |
| Variant type | single nucleotide variant |
| Location | chr1:236825373-236825373 (GRCh38) |
| ClinVar | [VCV452126](https://www.ncbi.nlm.nih.gov/clinvar/variation/452126/) |

**All HGVS expressions:** `NC_000001.10:g.236988673C>G`, `NC_000001.11:g.236825373C>G`, `NG_008959.1:g.35093C>G`, `NM_000254.3:c.901C>G`, `NM_001291939.1:c.901C>G`, `NM_001291940.2:c.-208C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0741)
- REVEL 0.331 (indeterminate)
- SaProt LLR -3.783 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.537, GERP 2.77, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.81** across the covering region of the MANE Select transcript (236,795,704–236,897,641), spanning 101,937 bp. Chi-square p 9.3e-14. 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 **0.00695%** (nfe) · FAF95 0.00571% · FAF99 0.00525% · 82/1,179,762 in the highest group · 83/1,613,634 alleles overall — very rare (popmax 0.00695%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00695% | 14,387 |
| Admixed American | 0.00167% | 59,994 |

*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 30, triplosensitivity 0 (0–3 scale). *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 **301** lies in the hcy-binding domain.

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. p.Pro301Ala falls in the hcy-binding domain. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-03-12.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2017–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-09-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Methylcobalamin deficiency type cblG, not provided, none provided, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE, Functional methionine synthase deficiency type cblG, HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE.

## Same-residue context {#hotspot}

Residue **301** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MTR p.Pro301fs](/variant/mtr-p-pro301fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MTR variant pages (same residue, condition, or type): [MTR p.Pro301Ser](/variant/mtr-p-pro301ser), [MTR p.Pro301fs](/variant/mtr-p-pro301fs), [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).

### 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 2026-07-14); 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 452126). 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.*