Is DNMT3A p.Cys562Arg (c.1684T>C) pathogenic?

DNMT3A p.Cys562Arg (c.1684T>C) is classified Conflicting classifications of pathogenicity in DNMT3A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-04-03). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Cys562Arg (c.1684T>C)?

DNMT3A p.Cys562Arg (c.1684T>C) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Cys562Arg (c.1684T>C) in the general population?

DNMT3A p.Cys562Arg (c.1684T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Cys562Arg (c.1684T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

DNMT3A p.Cys562Arg

c.1684T>C · rs1057520788 · VCV379924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 7% in DNMT3A
REVEL	0.961	strongly pathogenic-leaning
SaProt	LLR -14.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT3A
Protein: p.Cys562Arg
Coding: c.1684T>C
MANE Select: NM_022552
dbSNP: rs1057520788
Type: single nucleotide variant
Location: chr2:25244322 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 562: 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.Cys562Gly 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
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-cys562arg (accessed [today's date]).

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