Is DNMT3A p.Glu599Ala (c.1796A>C) pathogenic?

DNMT3A p.Glu599Ala (c.1796A>C) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-02). AlphaMissense: likely benign (0.1092); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Glu599Ala (c.1796A>C)?

DNMT3A p.Glu599Ala (c.1796A>C) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT3A p.Glu599Ala (c.1796A>C) in the general population?

DNMT3A p.Glu599Ala (c.1796A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Glu599Ala (c.1796A>C)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

DNMT3A p.Glu599Ala

c.1796A>C · VCV3841808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -10.17	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT3A
Protein: p.Glu599Ala
Coding: c.1796A>C
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25244210 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 599: the add domain

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

Similar variants

DNMT3A p.Glu599Asp Likely benign ★ ⚠ same residue
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg688His Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Met548Thr Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Pro904Leu Pathogenic/Likely pathogenic ★★ same condition
DNMT3A c.448+48C>G Uncertain significance ★★ same condition
DNMT3A p.Arg544His 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-glu599ala (accessed [today's date]).

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