Is DNMT3A p.Arg749Ser (c.2245C>A) pathogenic?

DNMT3A p.Arg749Ser (c.2245C>A) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9874); Very rare (popmax 0.000254%, nfe); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Arg749Ser (c.2245C>A)?

DNMT3A p.Arg749Ser (c.2245C>A) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Arg749Ser (c.2245C>A) in the general population?

DNMT3A p.Arg749Ser (c.2245C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Arg749Ser (c.2245C>A)?

AlphaMissense predicts likely pathogenic (score 0.9874) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg749Ser

c.2245C>A · rs754613602 · VCV2422011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.9874	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -10.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 4,806 bp · p 8.9e-10 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,924 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,714 alleles · very rare

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.Arg749Ser
Coding: c.2245C>A
MANE Select: NM_022552
dbSNP: rs754613602
Type: single nucleotide variant
Location: chr2:25240379 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 749: the sam-dependent mtase c5-type domain; a UniProt-annotated variant site (in tbrs; somatic mutation)

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 p.Arg749Cys Pathogenic ★★ same residue
DNMT3A p.Arg749Leu 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

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-arg749ser (accessed [today's date]).

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