MTR

Chr 1AR

5-methyltetrahydrofolate-homocysteine methyltransferase

Also known as: HMAG, MS, cblG

NCBI Gene: 4548 ENSG00000116984 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…

LOFmechanismARLOEUF 0.632 OMIM phenotypes

Clinical Summary— MTR

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Gene-Disease Validity (ClinGen)

methylcobalamin deficiency type cblG · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

108 unique Pathogenic / Likely Pathogenic· 414 VUS of 1477 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMTR-related methylcobalamin deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6743th %ile

GOF

0.5464th %ile

LOF

0.2678th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1477 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64

Likely Pathogenic44

VUS414

Likely Benign709

Benign170

Conflicting40

Pathogenic

Likely Pathogenic

414

VUS

709

Likely Benign

170

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	3	5	0	64
Likely Pathogenic	36	5	3	0	44
VUS	2	269	135	8	414
Likely Benign	2	11	370	326	709
Benign	0	6	156	8	170
Conflicting	—				40
Total	96	294	669	342	1,441

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

47 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap MTR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

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

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GeneReview available — MTR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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 (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

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

Organic AcidemiaMethylmalonic AcidemiaInborn Errors of Metabolism

Clinical and Laboratory Study of Methylmalonic Acidemia

RECRUITING

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

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