DNMT1

Chr 19AD

DNA methyltransferase 1

ENSG00000130816 UniProt: P26358 OMIM: 126375

This gene encodes DNA methyltransferase 1, the primary enzyme responsible for maintaining DNA methylation patterns during replication, which is essential for epigenetic gene regulation. Mutations cause autosomal dominant cerebellar ataxia with deafness and narcolepsy, and hereditary sensory neuropathy type IE. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0), reflecting its critical role in cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

DNA methyltransferase that methylates CpG residues (PubMed:17200670, PubMed:18754681, PubMed:21745816, PubMed:26070743). Preferentially methylates hemimethylated DNA (PubMed:21745816, PubMed:26070743). Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance (PubMed:17200670, PubMed:21745816). Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication (PubMed:21745816). It is responsible for maintaining methylation patterns established in development (PubMed:21745816). DNA methylation is coordinated with methylation of histones (PubMed:16357870). Mediates transcriptional repression by direct binding to HDAC2 (PubMed:10888872). In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9 (PubMed:18413740). Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306)

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.142 OMIM phenotypes

Clinical Summary— DNMT1

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Gene-Disease Validity (ClinGen)

autosomal dominant cerebellar ataxia, deafness and narcolepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 282 VUS of 695 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 8.21

OE 0.08 (0.04–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.99Z-score

OE missense 0.55 (0.51–0.59)

537 obs / 975.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.14)

0≤0.351.4

Missense OE?0.55 (0.51–0.59)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 7 / 91.9Missense obs/exp: 537 / 975.6Syn Z: -0.36

This gene — mechanism propensity

0.2199th %ile

GOF

0.2099th %ile

LOF

0.77top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.14

Literature Evidence

LOFUsing behavioral tests, we demonstrated that Dnmt1 haploinsufficiency impairs learning and memory functions in an age-dependent manner.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 22704347 ↗

ClinVar Variant Classifications

695 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5

VUS282

Likely Benign319

Benign27

Conflicting25

Likely Pathogenic

282

VUS

319

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	5	0	0	5
VUS	5	246	24	7	282
Likely Benign	0	13	153	153	319
Benign	0	3	15	9	27
Conflicting	—				25
Total	5	267	192	169	658

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

View in ClinVar →

4 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap DNMT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

DNMT1 · 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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

BRCA1 MutationBRCA2 MutationBRCA Mutation

Olaparib and ASTX727 in BRCA1/2- and Homologous Recombination Deficient (HRD)-Mutated Tumors

RECRUITING

NCT06177171Phase PHASE1Varun Monga, MBBSStarted 2024-02-07

OlaparibASTX727

Peripheral T Cells Lymphoma (PTCL)

Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCL

RECRUITING

NCT07372352Phase PHASE2The First Affiliated Hospital of Soochow UniversityStarted 2026-01-15

ZeprumetostatAzacitidine (AZA)Mitoxantrone Hydrochloride Liposome

Polycystic Ovary Syndrome

Ovary Syndrome for Efficient Diagnosis and Targeted Therapy

NOT YET RECRUITING

NCT06102629Phase NAAsian Institute of Gastroenterology, IndiaStarted 2023-11-05

laparoscopy / laparotomyNO INTERVENTION

Overweight and ObesityLupus Erythematosus

Methyl-donor Nutrient Supplementation and Methylation Profile in Lupus Patients With Obesity

ENROLLING BY INVITATION

NCT05097365Phase NAUniversity of Sao PauloStarted 2022-01-01

Vitamin B12 + folic acid supplementationPlacebo supplementation

NeoplasmsSolid Tumors

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors

RECRUITING

NCT03366116Phase PHASE1National Cancer Institute (NCI)Started 2018-11-05

aza-TdC

Glioma

Clinical Study for the Safety and Therapeutic Efficacy of the AI-QMMM Designed TamavaqTM Personalised Vaccine in Patients With Newly Diagnosed Glioma.

RECRUITING

NCT07077616Phase EARLY_PHASE1Biogenea Pharmaceuticals Ltd.Started 2025-07-01

Biological: personalized vaccine Based on genetic and transcriptional sequencing information, personalized peptide vaccines would be designed and produced;

Glioblastoma, IDH-wildtypeMGMT-Methylated Glioblastoma

Lomustine in Addition to Standard of Care in Patients With MGMT Methylated Glioblastoma

RECRUITING

NCT06419946Phase PHASE3Vastra Gotaland RegionStarted 2025-02-01

TemozolomideLomustine

Glioblastoma

A Study Using Radiation Therapy and Temozolomide to Treat Glioblastoma in Patients Over 70

ACTIVE NOT RECRUITING

NCT01985087Phase PHASE1, PHASE2University of LouisvilleStarted 2014-09