Is DNMT3A p.Cys559= (c.1677C>T) pathogenic?

DNMT3A p.Cys559= (c.1677C>T) is classified Benign/Likely benign in DNMT3A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-21). Ultra-rare (popmax 0.0514%, amr); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Cys559= (c.1677C>T)?

DNMT3A p.Cys559= (c.1677C>T) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Cys559= (c.1677C>T) in the general population?

DNMT3A p.Cys559= (c.1677C>T) is ultra-rare (popmax 0.0514%, amr) (gnomAD).

DNMT3A p.Cys559=

c.1677C>T · rs775908350 · VCV772037

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0514%, amr)

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -3.7
Overall
CADD	5.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0514% Admixed American · 30/58,320 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.0254% 408/1,605,268 alleles · ultra-rare exomes 365/1,453,192 · genomes 43/152,076 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.146%	684
Remaining individualsnot grpmax-eligible	0.0548%	1,826
Admixed Americangrpmax	0.0514%	1,944
South Asian	0.0388%	2,575
Middle Eastern	0.033%	3,032
European (non-Finnish)	0.0209%	4,781
Finnishnot grpmax-eligible	0.0174%	5,732
African / African-American	0.00803%	12,450
East Asian	0.00225%	44,442

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys559=
Coding: c.1677C>T
MANE Select: NM_022552
dbSNP: rs775908350
Type: single nucleotide variant
Location: chr2:25244329 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 559: the 'interaction with the prc2/eed-ezh2 complex' region; the add domain; a β-strand

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.Cys559Arg Uncertain significance ★ ⚠ same residue
DNMT3A p.Cys559Tyr 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.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-cys559 (accessed [today's date]).

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