MTHFD1L

Chr 6

methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like

NCBI Gene: 25902ENSG00000120254UniProt: Q6UB35

May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism complementing thus the enzymatic activities of MTHFD2

178
ClinVar variants
20
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MTHFD1L
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 152 VUS of 178 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.
0.73LOEUF
pLI 0.000
Z-score 3.17
OE 0.53 (0.39–0.73)
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.
0.99Z-score
OE missense 0.88 (0.81–0.95)
459 obs / 522.8 exp
Tolerant

Mild missense constraint

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.0.53 (0.39–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.81–0.95)
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.1.02
0≤1.21.6
LoF obs/exp: 28 / 52.9Missense obs/exp: 459 / 522.8Syn Z: -0.23

ClinVar Variant Classifications

178 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
VUS152
Likely Benign5
Benign1
20
Pathogenic
152
VUS
5
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
0
0
0
0
VUS
0
148
4
0
152
Likely Benign
0
3
2
0
5
Benign
0
0
0
1
1
Total0151261178

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

View in ClinVar →

Protein Context — Lollipop Plot

MTHFD1L · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Activated brown adipose tissue releases exosomes containing mitochondrial methylene tetrahydrofolate dehydrogenase (NADP dependent) 1-like protein (MTHFD1L).
Leow MK et al.·Biosci Rep
2022
Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L-formate axis.
Cui L et al.·J Pineal Res
2021Functional
Integrated bioinformatics analysis identified MTHFD1L as a potential biomarker and correlated with immune infiltrates in hepatocellular carcinoma.
Chen J et al.·Biosci Rep
2021
Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression.
Eszlari N et al.·Transl Psychiatry
2016Functional
Rs6922269 marker at the MTHFD1L gene predict cardiovascular mortality in males after acute coronary syndrome.
Hubacek JA et al.·Mol Biol Rep
2015
Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential.
Zhao LN et al.·Oncogene
2021Review
Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer.
Do SK et al.·Oncology
2020
Expression, Prognostic Value, and Immune Infiltration of MTHFD Family in Bladder Cancer.
Zheng BS et al.·Curr Cancer Drug Targets
2024
Whole Exome Sequencing Identifies Damaging Variants in Indonesians with Clefts.
Aladenika E et al.·Cleft Palate Craniofac J
2025
Unraveling the genetic basis of subclinical atherosclerosis: Early genetic detection can improve cardiovascular prevention.
Sá D et al.·Rev Port Cardiol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Toremifene exerts chemopreventive effects against breast cancer through MTHFD1L suppression and ROS-mediated apoptosis.
Chen L et al.·Chin Med J (Engl)
2025
MTHFD1L is a novel prognostic marker and therapeutic target in cutaneous melanoma.
Xie X et al.·Diagn Pathol
2025🔓 Open Access
Optical coherence tomography-guided Brillouin microscopy highlights regional tissue stiffness differences during anterior neural tube closure in the Mthfd1l murine mutant.
Ambekar YS et al.·Development
2024
Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation.
Tsai YC et al.·Am J Cancer Res
2024
MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway.
Zhou J et al.·Exp Cell Res
2023
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