DNMT1

Chr 19AD

DNA methyltransferase 1

Also known as: ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT, m.HsaI

NCBI Gene: 1786 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

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

2 unique Pathogenic / Likely Pathogenic· 273 VUS of 600 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 →

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 OE0.08 (0.04–0.14)

0≤0.351.4

Missense OE0.55 (0.51–0.59)

0≤0.61.4

Synonymous OE1.02

0≤1.21.6

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

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.PMID:22704347

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

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS273

Likely Benign308

Benign11

Conflicting4

Pathogenic

273

VUS

308

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	2	0	2
Likely Pathogenic	0	0	0	0	0
VUS	6	235	26	6	273
Likely Benign	0	7	155	146	308
Benign	0	1	7	3	11
Conflicting	—				4
Total	6	243	190	155	598

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

View in ClinVar →

Protein Context — Lollipop Plot

DNMT1 · 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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

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

Hypofractionated radiotherapyTemozolomide

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

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

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;

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

BRCA1 MutationBRCA2 MutationBRCA Mutation

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

RECRUITING

NCT06177171Phase PHASE1Pamela MunsterStarted 2024-02-07