Is DNMT3A p.Ala571fs (c.1711dup) pathogenic?

DNMT3A p.Ala571fs (c.1711dup) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-21). Very rare (popmax 0.00134%, afr); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Ala571fs (c.1711dup)?

DNMT3A p.Ala571fs (c.1711dup) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Ala571fs (c.1711dup) in the general population?

DNMT3A p.Ala571fs (c.1711dup) is very rare (popmax 0.00134%, afr) (gnomAD).

DNMT3A p.Ala571fs

c.1711dup · rs1558665485 · VCV1072186

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 15 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,694 alleles

Overall 0.000659% 1/151,818 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.Ala571fs
Coding: c.1711dup
MANE Select: NM_022552
dbSNP: rs1558665485
Type: Duplication
Location: chr2:25244294 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 571: the 'interaction with the prc2/eed-ezh2 complex' region; the add domain; an α-helix

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.Ala571= Likely benign ★★ same residue
DNMT3A p.Ala571Thr Uncertain significance ★ ⚠ same residue
DNMT3A p.Val60fs Pathogenic ★★ same condition
DNMT3A p.Glu733Ter Pathogenic ★ same condition
DNMT3A p.Gly512fs Pathogenic ★ same condition
DNMT3A p.Phe414fs Pathogenic ★ same condition
DNMT3A p.Tyr526Ter Pathogenic ★ same condition
DNMT3A p.Pro453fs Uncertain significance ★ 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-ala571fs (accessed [today's date]).

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