MTR

Chr 1AR

5-methyltetrahydrofolate-homocysteine methyltransferase

Also known as: HMAG, MS, cblG

NCBI Gene: 4548ENSG00000116984UniProt: Q99707OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
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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Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

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 OE0.46 (0.35–0.63)
0≤0.351.4
Missense OE0.78 (0.72–0.84)
0≤0.61.4
Synonymous OE1.05
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

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

DN
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

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.

3D Protein StructureAlphaFold

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