Is DNMT3A p.Arg169Leu (c.506G>T) pathogenic?

DNMT3A p.Arg169Leu (c.506G>T) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-22). AlphaMissense: ambiguous (0.4721); Absent from gnomAD v4.1.

How common is DNMT3A p.Arg169Leu (c.506G>T) in the general population?

DNMT3A p.Arg169Leu (c.506G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Arg169Leu (c.506G>T)?

AlphaMissense predicts ambiguous (score 0.4721) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg169Leu

c.506G>T · VCV3900073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4721 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,589,588)

Computational evidence

Protein change
AlphaMissense	0.4721	ambiguous
REVEL	0.536	indeterminate
SaProt	LLR -6.51	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 27 kb · p 6.6e-12 · regional, not allelic
Overall
CADD	25.1	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

No allele count reported in gnomAD v4.1 (AN 1,589,588). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DNMT3A
Protein: p.Arg169Leu
Coding: c.506G>T
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25275074 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 169: the 'disordered' region

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

Similar variants

DNMT3A p.Arg169Trp Uncertain significance ★★ ⚠ same residue
DNMT3A c.1667+1G>A Likely pathogenic ★★ same type
DNMT3A c.1937-2A>G Pathogenic ★★ same type
DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same type
DNMT3A c.2479-1G>A Likely pathogenic ★★ same type
DNMT3A p.Arg143Ter Pathogenic ★★ same type
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same type

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-arg169leu (accessed [today's date]).

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