Is DNMT3A p.Ala449Thr (c.1345G>A) pathogenic?

DNMT3A p.Ala449Thr (c.1345G>A) is classified Uncertain significance in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0756); Ultra-rare (popmax 0.0121%, sas); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Ala449Thr (c.1345G>A)?

DNMT3A p.Ala449Thr (c.1345G>A) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Ala449Thr (c.1345G>A) in the general population?

DNMT3A p.Ala449Thr (c.1345G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about DNMT3A p.Ala449Thr (c.1345G>A)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

DNMT3A p.Ala449Thr

c.1345G>A · rs745406398 · VCV992734

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -4.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0121% South Asian · 11/91,066 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000929% 15/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
African / African-American	0.00133%	74,908
European (non-Finnish)	0.000254%	393,328

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.Ala449Thr
Coding: c.1345G>A
MANE Select: NM_022552
dbSNP: rs745406398
Type: single nucleotide variant
Location: chr2:25246244 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 449: 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

Similar variants

DNMT3A p.Ala449Ser Uncertain significance ★ ⚠ same residue
DNMT3A p.Ala449Val Uncertain significance ★ ⚠ same residue
DNMT3A p.Ala449= Likely benign ★ 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

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-ala449thr (accessed [today's date]).

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