Is DNMT3A p.Glu40= (c.120G>A) pathogenic?

DNMT3A p.Glu40= (c.120G>A) is classified Benign/Likely benign in DNMT3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.93%, sas); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Glu40= (c.120G>A)?

DNMT3A p.Glu40= (c.120G>A) is associated with Tatton-Brown-Rahman overgrowth syndrome, acute myeloid leukemia, Heyn-Sproul-Jackson syndrome (ClinVar).

How common is DNMT3A p.Glu40= (c.120G>A) in the general population?

DNMT3A p.Glu40= (c.120G>A) is low-frequency (popmax 1.93%, sas) (gnomAD).

DNMT3A p.Glu40=

c.120G>A · rs202118149 · VCV707468

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.93%, sas)

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.53, phastCons 1
Overall
CADD	9.059	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.93% South Asian · 1,756/91,072 alleles

Filtering AF 1.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.82%

Overall 0.113% 1,818/1,612,232 alleles · low-frequency exomes 1,727/1,459,964 · genomes 91/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.93%	52
Remaining individualsnot grpmax-eligible	0.0816%	1,225
Middle Eastern	0.0165%	6,060
East Asian	0.00446%	22,433
African / African-American	0.00133%	75,046
European (non-Finnish)	0.000593%	168,569

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.Glu40=
Coding: c.120G>A
MANE Select: NM_022552
dbSNP: rs202118149
Type: single nucleotide variant
Location: chr2:25300196 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 40: the 'disordered' 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

Also linked: acute myeloid leukemia Heyn-Sproul-Jackson syndrome

Similar variants

DNMT3A p.Glu40Asp Uncertain significance ★ ⚠ same residue
DNMT3A c.1667+1G>A Likely pathogenic ★★ same condition
DNMT3A c.1937-2A>G Pathogenic ★★ same condition
DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNMT3A c.2479-1G>A Likely pathogenic ★★ same condition
DNMT3A p.Arg143Ter Pathogenic ★★ same condition
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter 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-glu40 (accessed [today's date]).

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