Is DNMT3A p.Arg19Gln (c.56G>A) pathogenic?

DNMT3A p.Arg19Gln (c.56G>A) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-30). AlphaMissense: likely benign (0.0873); Very rare (popmax 0.00244%, nfe); Associated with intellectual disability.

What condition is associated with DNMT3A p.Arg19Gln (c.56G>A)?

DNMT3A p.Arg19Gln (c.56G>A) is associated with intellectual disability (ClinVar).

How common is DNMT3A p.Arg19Gln (c.56G>A) in the general population?

DNMT3A p.Arg19Gln (c.56G>A) is very rare (popmax 0.00244%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Arg19Gln (c.56G>A)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg19Gln

c.56G>A · VCV4075281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 0.0076 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00244% European (non-Finnish) · 28/1,147,078 alleles

Filtering AF 0.00169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.00194% 30/1,549,778 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00244%	40,967
East Asian	0.00243%	41,170
Remaining individualsnot grpmax-eligible	0.00167%	59,918

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.Arg19Gln
Coding: c.56G>A
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25313929 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 19: the 'disordered' region

Full DNMT3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A p.Arg19Trp Uncertain significance ★★ ⚠ same residue
DNMT3A p.Arg143Ter Pathogenic ★★ same condition
DNMT3A p.Arg882His Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Trp860Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Tyr908Asn Likely pathogenic ★ same condition
DNMT3A p.Arg736Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
DNMT3A p.Gly332Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
DNMT3A p.Glu235fs 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-arg19gln (accessed [today's date]).

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