Is DNMT3A p.Phe414fs (c.1238dup) pathogenic?

DNMT3A p.Phe414fs (c.1238dup) is classified Pathogenic in DNMT3A (ClinVar, Single submitter, 3 submitters; last evaluated 2018-12-12). Very rare (popmax 0.00127%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Phe414fs (c.1238dup)?

DNMT3A p.Phe414fs (c.1238dup) is associated with Inborn genetic diseases, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Phe414fs (c.1238dup) in the general population?

DNMT3A p.Phe414fs (c.1238dup) is very rare (popmax 0.00127%, nfe) (gnomAD).

DNMT3A p.Phe414fs

c.1238dup · rs755744291 · VCV985294

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

Inborn genetic diseases

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 10 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.4	GERP -3.4
Overall
CADD	34.0	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 0.00127% European (non-Finnish) · 15/1,179,860 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,613,190 alleles · very rare exomes 17/1,460,990 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Finnishnot grpmax-eligible	0.00315%	31,709
European (non-Finnish)grpmax	0.00127%	78,657
South Asian	0.0011%	91,074

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe414fs
Coding: c.1238dup
MANE Select: NM_022552
dbSNP: rs755744291
Type: Duplication
Location: chr2:25246660 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tatton-Brown-Rahman overgrowth syndrome

Similar variants

DNMT3A p.Phe414= Likely benign ★★ same residue
DNMT3A p.Ala571fs Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Val60fs Pathogenic ★★ same condition
DNMT3A p.Glu733Ter Pathogenic ★ same condition
DNMT3A p.Gly512fs Pathogenic ★ same condition
DNMT3A p.Leu639fs Pathogenic ★ same condition
DNMT3A p.Tyr526Ter Pathogenic ★ same condition
DNMT3A p.Pro453fs Uncertain significance ★ 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-phe414fs (accessed [today's date]).

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