Is DNMT3A p.Asp333= (c.999C>T) pathogenic?

DNMT3A p.Asp333= (c.999C>T) is classified Likely benign in DNMT3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Asp333= (c.999C>T)?

DNMT3A p.Asp333= (c.999C>T) is associated with Inborn genetic diseases, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Asp333= (c.999C>T) in the general population?

DNMT3A p.Asp333= (c.999C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

DNMT3A p.Asp333=

c.999C>T · rs148655749 · VCV2868527

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

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 -0.009	GERP -1.4, phastCons 0.17
Overall
CADD	11.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,848 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,613,776 alleles · very rare exomes 21/1,461,778 · genomes 3/151,998 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,712
Admixed American	0.00334%	29,981
East Asian	0.00223%	44,868
South Asian	0.0022%	45,527
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00119%	84,284

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.Asp333=
Coding: c.999C>T
MANE Select: NM_022552
dbSNP: rs148655749
Type: single nucleotide variant
Location: chr2:25247606 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 333: the pwwp domain; a UniProt-annotated variant site (in hesjas; changed dna methylation; results in aberrant expression of genes involved in developmental processes); a turn; the 'interaction with dnmt1 and dnmt3b' region

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

Also linked: Tatton-Brown-Rahman overgrowth syndrome

Similar variants

DNMT3A p.Asp333Asn Likely pathogenic ★ 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.Arg301Trp Pathogenic/Likely 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-asp333 (accessed [today's date]).

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