Is DNMT3A p.Ala254fs (c.754_760dup) pathogenic?

DNMT3A p.Ala254fs (c.754760dup) is classified Pathogenic in DNMT3A (ClinVar, No assertion criteria, 1 submitter). Absent from gnomAD; Associated with EBV-positive nodal T- and NK-cell lymphoma.

What condition is associated with DNMT3A p.Ala254fs (c.754_760dup)?

DNMT3A p.Ala254fs (c.754_760dup) is associated with EBV-positive nodal T- and NK-cell lymphoma (ClinVar).

How common is DNMT3A p.Ala254fs (c.754_760dup) in the general population?

DNMT3A p.Ala254fs (c.754_760dup) is absent from gnomAD (gnomAD).

DNMT3A p.Ala254fs

c.754_760dup · rs2465573611 · VCV2681242

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

EBV-positive nodal T- and NK-cell lymphoma

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 7 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 0.85, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Ala254fs
Coding: c.754_760dup
MANE Select: NM_022552
dbSNP: rs2465573611
Type: Duplication
Location: chr2:25248131 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 254: the 'interaction with dnmt1 and dnmt3b' region; the 'disordered' region

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

Disease context

EBV-positive nodal T- and NK-cell lymphoma

Similar variants

DNMT3A p.Arg659fs Likely pathogenic ★ same condition
DNMT3A p.Arg771fs Pathogenic ★ same condition
DNMT3A p.Pro602fs Likely pathogenic ★ same condition
DNMT3A p.His588fs Likely pathogenic same condition
DNMT3A p.Ile539fs Likely pathogenic same condition
DNMT3A c.640-3735dup Uncertain significance same condition
DNMT3A c.1667+1G>A Likely pathogenic ★★ same condition
DNMT3A p.Arg771Ter 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-ala254fs (accessed [today's date]).

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