MTRR

Chr 5AR

5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Also known as: MSR, cblE

NCBI Gene: 4552ENSG00000124275UniProt: Q9UBK8

This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

{Neural tube defects, folate-sensitive, susceptibility to}MIM #601634
AR
Homocystinuria-megaloblastic anemia, cbl E typeMIM #236270
AR
473
ClinVar variants
72
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MTRR
🧬
Gene-Disease Validity (ClinGen)
methylcobalamin deficiency type cblE · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
72 Pathogenic / Likely Pathogenic· 175 VUS of 473 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.98LOEUF
pLI 0.000
Z-score 1.64
OE 0.71 (0.52–0.98)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.67Z-score
OE missense 1.10 (1.01–1.19)
423 obs / 386.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.71 (0.52–0.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.10 (1.01–1.19)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.14
0≤1.21.6
LoF obs/exp: 27 / 37.9Missense obs/exp: 423 / 386.2Syn Z: -1.38

ClinVar Variant Classifications

473 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic30
VUS175
Likely Benign212
Benign13
Conflicting1
42
Pathogenic
30
Likely Pathogenic
175
VUS
212
Likely Benign
13
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
29
0
42
Likely Pathogenic
20
1
9
0
30
VUS
1
162
10
2
175
Likely Benign
1
7
93
111
212
Benign
0
0
13
0
13
Conflicting
—1
Total35170154113473

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

View in ClinVar →

Protein Context — Lollipop Plot

MTRR · protein map & ClinVar variants

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

Gene2Phenotype Curations

MTRR-related homocystinuria-megaloblastic anemia, cblE type

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Neural tube defects, folate-sensitive, susceptibility to}

MIM #601634

Molecular basis of disorder known

Autosomal recessive

Homocystinuria-megaloblastic anemia, cbl E type

MIM #236270

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MTRR
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms.
Zhang C et al.·Nutrients
2025
Homocysteine Exacerbates Pulmonary Fibrosis via Orchestrating Syntaxin 17 Homocysteinylation of Alveolar Type II Cells.
Huang J et al.·Adv Sci (Weinh)
2025
Genetic variant in MTRR, but not MTR, is associated with risk of congenital heart disease: an integrated meta-analysis.
Cai B et al.·PLoS One
2014Meta-analysis
Antimicrobial-resistant Neisseria gonorrhoeae in Europe in 2020 compared with in 2013 and 2018: a retrospective genomic surveillance study.
Golparian D et al.·Lancet Microbe
2024
The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival.
Wang Y et al.·Nutrients
2022
Folate metabolism abnormalities in infertile patients with endometriosis.
Guedes T et al.·Biomark Med
2022Cohort
The common homocystinuria-associated P1173L variant of human methionine synthase impairs reductive methylation.
Guha A et al.·J Biol Chem
2025
Characteristics of Neisseria meningitidis isolated from patients with urogenital infection in a region of China.
Xie Q et al.·Ann Clin Microbiol Antimicrob
2025Cohort
Folate and cobalamin status, indicators, modulators, interactions, and reference ranges from early pregnancy until birth: the Reus-Tarragona birth cohort study.
Santos-Calderón LA et al.·Am J Clin Nutr
2024Cohort
The association between methionine synthase reductase c.66A>G variant and the risk of recurrent pregnancy loss: A systematic review and meta-analysis.
Zhou J et al.·J Gynecol Obstet Hum Reprod
2024Meta-analysis
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
MtrR Regulates a Major Lytic Transglycosylase (ltgA) Responsible for Peptidoglycan-Derived Cytotoxin Release and Autolysis in Neisseria gonorrhoeae.
Telchy AI et al.·Microorganisms
2026
H2-dependent modulation of tetrahydromethanopterin S-methyltransferase (Mtr complex) activity by the small protein MtrR in Methanosarcina mazei.
Habenicht T et al.·FEBS J
2026
MTHFR and MTRR Polymorphisms Predict Sex-Dependent Psychotic Symptom Improvements, Not Metabolic Changes.
Nadalin S et al.·Int J Mol Sci
2026🔓 Open Access
Correlation of supplement folic acid based on MTHFR and MTRR gene polymorphisms with preeclampsia in Chinese population: an retrospective cohort study.
Xiong X et al.·Front Nutr
2025🔓 Open AccessCohort
Association analysis of MTHFR (C677T, A1298C) and MTRR (A66G) gene polymorphisms on susceptibility to gestational diabetes mellitus in Chinese pregnant women.
Han W et al.·Gynecol Endocrinol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools