Is DNMT3A p.Phe354fs (c.1060_1069del) pathogenic?

DNMT3A p.Phe354fs (c.10601069del) is classified Pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-19). Absent from gnomAD; Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Phe354fs (c.1060_1069del)?

DNMT3A p.Phe354fs (c.1060_1069del) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Phe354fs (c.1060_1069del) in the general population?

DNMT3A p.Phe354fs (c.1060_1069del) is absent from gnomAD (gnomAD).

DNMT3A p.Phe354fs

c.1060_1069del · rs1558671136 · VCV569775

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Tatton-Brown-Rahman overgrowth syndrome

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 9 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.4, 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.Phe354fs
Coding: c.1060_1069del
MANE Select: NM_022552
dbSNP: rs1558671136
Type: Deletion
Location: chr2:25247104 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 354: the 'interaction with dnmt1 and dnmt3b' region

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

Disease context

Tatton-Brown-Rahman overgrowth syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A c.1123del Pathogenic ★ same condition
DNMT3A p.Ala246fs Pathogenic ★ same condition
DNMT3A p.Arg598fs Pathogenic ★ same condition
DNMT3A p.Arg891fs Pathogenic ★ same condition
DNMT3A p.Asp11fs Pathogenic ★ same condition
DNMT3A p.Asp394fs Pathogenic ★ same condition
DNMT3A p.Cys583fs Pathogenic ★ same condition
DNMT3A p.Gln415fs 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-phe354fs (accessed [today's date]).

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