DOT1L

Chr 19

DOT1 like histone lysine methyltransferase

Also known as: DOT1, KMT4, NDNS

NCBI Gene: 84444 ENSG00000104885 UniProt: Q8TEK3

The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes. [provided by RefSeq, Aug 2011]

Research

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.12

Clinical Summary— DOT1L

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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

9 unique Pathogenic / Likely Pathogenic· 233 VUS of 358 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 7.17

OE 0.05 (0.02–0.12)

Highly constrained

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

Missense Constraint?

2.72Z-score

OE missense 0.75 (0.71–0.80)

736 obs / 975.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.75 (0.71–0.80)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 3 / 65.8Missense obs/exp: 736 / 975.5Syn Z: -3.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDOT1L-related neurodevelopmental disorder with intracranial anomaliesGOFAD

This gene — mechanism propensity

0.2599th %ile

GOF

0.2696th %ile

LOF

0.86top 5%

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

LOFprediction above median · LOEUF 0.12

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

358 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic1

VUS233

Likely Benign70

Benign11

Conflicting1

Pathogenic

Likely Pathogenic

233

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	8	0	0	8
Likely Pathogenic	1	0	0	0	1
VUS	17	214	2	0	233
Likely Benign	0	42	1	27	70
Benign	0	1	3	7	11
Conflicting	—				1
Total	18	265	6	34	324

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap DOT1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →