Is DNMT3A p.Lys299fs (c.894del) pathogenic?

DNMT3A p.Lys299fs (c.894del) is classified Likely pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Very rare (popmax 8.48e-05%, nfe); Associated with acute myeloid leukemia.

What condition is associated with DNMT3A p.Lys299fs (c.894del)?

DNMT3A p.Lys299fs (c.894del) is associated with acute myeloid leukemia (ClinVar).

How common is DNMT3A p.Lys299fs (c.894del) in the general population?

DNMT3A p.Lys299fs (c.894del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

DNMT3A p.Lys299fs

c.894del · VCV4683101

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

acute myeloid leukemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,646 alleles

Overall 6.84e-05% 1/1,461,288 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DNMT3A
Protein: p.Lys299fs
Coding: c.894del
MANE Select: NM_022552
Type: Deletion
Location: chr2:25247711 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 299: the pwwp domain; the 'interaction with dnmt1 and dnmt3b' region

Full DNMT3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acute myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A p.Gly646fs Pathogenic ★ same condition
DNMT3A p.Lys299Gln Likely pathogenic ★ same residue
DNMT3A p.Lys299Ile Pathogenic ★ same residue
DNMT3A p.Lys299= Likely benign ★ same residue
DNMT3A p.Met345fs Likely pathogenic same condition
DNMT3A p.Arg771Gln Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg771Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg882Cys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dnmt3a-p-lys299fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown