MTR

Chr 1AR

5-methyltetrahydrofolate-homocysteine methyltransferase

Also known as: HMAG, MS, cblG

NCBI Gene: 4548 ENSG00000116984 UniProt: Q99707 OMIM: 156570

The 5-methyltetrahydrofolate-homocysteine methyltransferase catalyzes the final step in methionine biosynthesis as a cobalamin-dependent methionine synthase. Biallelic mutations cause homocystinuria-megaloblastic anemia (cblG complementation type) and increase susceptibility to neural tube defects through autosomal recessive inheritance. The pathogenic mechanism involves loss of enzyme function leading to impaired methionine synthesis and elevated homocysteine levels.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Neural tube defects, folate-sensitive, susceptibility to}MIM #601634

Homocystinuria-megaloblastic anemia, cblG complementation typeMIM #250940

Clinical highlights

Gene-disease validity (ClinGen)

methylcobalamin deficiency type cblG · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

303

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MTR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.000

Z-score 4.05

OE 0.46 (0.35–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.04Z-score

OE missense 0.78 (0.72–0.84)

527 obs / 676.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.46 (0.35–0.63)

0≤0.351.4

Missense OE?0.78 (0.72–0.84)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 31 / 66.7Missense obs/exp: 527 / 676.6Syn Z: -0.58

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

MTR · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — MTR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Breast NeoplasmsTriple Negative Breast NeoplasmsHR Low-Positive/HER2-Negative Breast Neoplasms

A Clinical Study of Sacituzumab Tirumotecan (Sac-TMT, MK-2870) in People With Breast Cancer (MK-2870-032)

RECRUITING

NCT06966700Phase PHASE3Merck Sharp & Dohme LLCStarted 2025-06-30

Sacituzumab tirumotecanPembrolizumabRescue Medication

Organic AcidemiaMethylmalonic AcidemiaInborn Errors of Metabolism

Clinical and Laboratory Study of Methylmalonic Acidemia

RECRUITING

NCT00078078National Human Genome Research Institute (NHGRI)Started 2004-06-07

Sickle Cell Disease (SCD)

Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients

ACTIVE NOT RECRUITING

NCT03814746Phase PHASE3Novartis PharmaceuticalsStarted 2019-07-26

Crizanlizumab (SEG101)Placebo

Colon AdenocarcinomaRectal Adenocarcinoma

A Clinical Study of Calderasib (MK-1084) With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012)

RECRUITING

NCT06997497Phase PHASE3Merck Sharp & Dohme LLCStarted 2025-07-16

CalderasibOxaliplatinLeucovorin/levofolinate calcium

Advanced Solid Neoplasms

Efficacy and Safety of Olaparib (MK-7339) in Participants With Previously Treated, Homologous Recombination Repair Mutation (HRRm) or Homologous Recombination Deficiency (HRD) Positive Advanced Cancer (MK-7339-002 / LYNK-002)

ACTIVE NOT RECRUITING

NCT03742895Phase PHASE2Merck Sharp & Dohme LLCStarted 2018-12-12

Olaparib

Sickle Cell Disease

A Study to Investigate the Efficacy and Safety of Crizanlizumab (5 mg/kg) Compared With Placebo in Adolescent and Adult Sickle Cell Disease Patients Who Experience Frequent Vaso-Occlusive Crises (SPARKLE)

RECRUITING

NCT06439082Phase PHASE3Novartis PharmaceuticalsStarted 2024-10-24

CrizanlizumabPlacebo

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Whitepaper: Anerkennung auslandischer MTR.

·Rofo

2026