Is DNMT3A p.Arg749Cys (c.2245C>T) pathogenic?

DNMT3A p.Arg749Cys (c.2245C>T) is classified Pathogenic in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.8732); Very rare (popmax 0.00178%, nfe); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Arg749Cys (c.2245C>T)?

DNMT3A p.Arg749Cys (c.2245C>T) is associated with Tatton-Brown-Rahman overgrowth syndrome, melanoma (ClinVar).

How common is DNMT3A p.Arg749Cys (c.2245C>T) in the general population?

DNMT3A p.Arg749Cys (c.2245C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Arg749Cys (c.2245C>T)?

AlphaMissense predicts likely pathogenic (score 0.8732) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg749Cys

c.2245C>T · rs754613602 · VCV2203023

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.8732	likely pathogenic ✓ concordant with ClinVar
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -12.39	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	34.0	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

Grpmax group 0.00178% European (non-Finnish) · 21/1,179,876 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,818 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,185
Remaining individualsnot grpmax-eligible	0.0016%	62,470
Finnishnot grpmax-eligible	0.00156%	64,006
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,088

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.Arg749Cys
Coding: c.2245C>T
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

Also linked: melanoma

Similar variants

DNMT3A p.Arg749Ser Uncertain significance ★ ⚠ 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-arg749cys (accessed [today's date]).

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