Is DNMT3A p.Ile780fs (c.2340_2343del) pathogenic?

DNMT3A p.Ile780fs (c.23402343del) is classified Likely pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-29). Absent from gnomAD v4.1; Associated with DNMT3A-related disorder.

What condition is associated with DNMT3A p.Ile780fs (c.2340_2343del)?

DNMT3A p.Ile780fs (c.2340_2343del) is associated with DNMT3A-related disorder (ClinVar).

How common is DNMT3A p.Ile780fs (c.2340_2343del) in the general population?

DNMT3A p.Ile780fs (c.2340_2343del) is absent from gnomAD v4.1 (gnomAD).

DNMT3A p.Ile780fs

c.2340_2343del · VCV4953969

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,980)

Conditions

DNMT3A-related disorder

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 20 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,980). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DNMT3A
Protein: p.Ile780fs
Coding: c.2340_2343del
MANE Select: NM_022552
Type: Microsatellite
Location: chr2:25239195 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 780: a β-strand; the sam-dependent mtase c5-type domain

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

Disease context

DNMT3A-related disorder

Similar variants

DNMT3A p.Ile780= Likely benign same residue
DNMT3A p.Phe732del Uncertain significance ★★ same condition
DNMT3A p.Ile780Thr Uncertain significance ★ ⚠ same residue
DNMT3A c.1851+2_1851+3del Uncertain significance same condition
DNMT3A c.2174-4_2174-3del Likely benign same condition
DNMT3A c.1667+1G>A Likely pathogenic ★★ same condition
DNMT3A p.Arg771Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Leu508Pro 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-ile780fs (accessed [today's date]).

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