Is DNMT3A p.Pro569Leu (c.1706C>T) pathogenic?

DNMT3A p.Pro569Leu (c.1706C>T) is classified Uncertain significance in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2618); Ultra-rare (popmax 0.0165%, mid); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Pro569Leu (c.1706C>T)?

DNMT3A p.Pro569Leu (c.1706C>T) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Pro569Leu (c.1706C>T) in the general population?

DNMT3A p.Pro569Leu (c.1706C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DNMT3A p.Pro569Leu (c.1706C>T)?

AlphaMissense predicts likely benign (score 0.2618) — an in-silico prediction, not a clinical call.

DNMT3A p.Pro569Leu

c.1706C>T · rs772310511 · VCV855198

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.2618	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -12.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.79, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	29.4	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 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000901%

Overall 0.00174% 28/1,610,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
South Asian	0.00441%	22,684
Admixed American	0.00336%	29,764
East Asian	0.00224%	44,738
European (non-Finnish)	0.0017%	58,942

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.Pro569Leu
Coding: c.1706C>T
MANE Select: NM_022552
dbSNP: rs772310511
Type: single nucleotide variant
Location: chr2:25244300 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 569: the 'interaction with the prc2/eed-ezh2 complex' region; the add domain

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.Pro569= 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
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter 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-pro569leu (accessed [today's date]).

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