Is DNMT3A p.Lys459fs (c.1374del) pathogenic?

DNMT3A p.Lys459fs (c.1374del) is classified Pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-10). Very rare (popmax 0.00133%, afr).

How common is DNMT3A p.Lys459fs (c.1374del) in the general population?

DNMT3A p.Lys459fs (c.1374del) is very rare (popmax 0.00133%, afr) (gnomAD).

DNMT3A p.Lys459fs

c.1374del · rs886041641 · VCV280432

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 11 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,926 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,926
European (non-Finnish)	0.000169%	589,998

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.Lys459fs
Coding: c.1374del
MANE Select: NM_022552
dbSNP: rs886041641
Type: Deletion
Location: chr2:25246215 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 459: the 'disordered' region

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

Similar variants

DNMT3A p.Lys459Arg Uncertain significance ★ ⚠ same residue
DNMT3A p.Lys459Gln Uncertain significance ★ ⚠ same residue
DNMT3A c.1123del Pathogenic ★ same type
DNMT3A p.Ala246fs Pathogenic ★ same type
DNMT3A p.Ala449fs Pathogenic ★ same type
DNMT3A p.Arg598fs Pathogenic ★ same type
DNMT3A p.Arg891fs Pathogenic ★ same type
DNMT3A p.Asp11fs Pathogenic ★ same type

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-lys459fs (accessed [today's date]).

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