Is DNMT3A p.Tyr481= (c.1443C>T) pathogenic?

DNMT3A p.Tyr481= (c.1443C>T) is classified Benign/Likely benign in DNMT3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). Rare (popmax 0.127%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Tyr481= (c.1443C>T)?

DNMT3A p.Tyr481= (c.1443C>T) is associated with Inborn genetic diseases, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Tyr481= (c.1443C>T) in the general population?

DNMT3A p.Tyr481= (c.1443C>T) is rare (popmax 0.127%, afr) (gnomAD).

DNMT3A p.Tyr481=

c.1443C>T · rs145465364 · VCV1250188

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.127%, 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 -1.2	GERP -3
Overall
CADD	5.163	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.127% African / African-American · 95/74,930 alleles

Filtering AF 0.106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0984%

Overall 0.00682% 110/1,614,004 alleles · rare exomes 59/1,461,806 · genomes 51/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.127%	789
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.000678%	147,500

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.Tyr481=
Coding: c.1443C>T
MANE Select: NM_022552
dbSNP: rs145465364
Type: single nucleotide variant
Location: chr2:25246051 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 481: an α-helix

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.Tyr481Ter 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-tyr481 (accessed [today's date]).

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