Is DNMT3A p.Asp22fs (c.64_66delinsAGCAG) pathogenic?

DNMT3A p.Asp22fs (c.6466delinsAGCAG) is classified Likely pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). Associated with DNMT3A-related disorder.

What condition is associated with DNMT3A p.Asp22fs (c.64_66delinsAGCAG)?

DNMT3A p.Asp22fs (c.64_66delinsAGCAG) is associated with DNMT3A-related disorder (ClinVar).

DNMT3A p.Asp22fs

c.64_66delinsAGCAG · VCV4953997

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 2 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1

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

Variant & gene context

Gene: DNMT3A
Protein: p.Asp22fs
Coding: c.64_66delinsAGCAG
MANE Select: NM_022552
Type: Indel
Location: chr2:25313919 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 22: the 'disordered' region

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

Disease context

DNMT3A-related disorder

Similar variants

DNMT3A p.Asp22Val Uncertain significance ⚠ same residue
DNMT3A p.Asp22= Likely benign same residue
DNMT3A p.Asp22Asn Uncertain significance ★ ⚠ same residue
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
DNMT3A p.Trp601Ter Pathogenic ★★ same condition
DNMT3A p.Val636Met 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-asp22fs (accessed [today's date]).

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