Is DNMT3A p.Arg659Cys (c.1975C>T) pathogenic?

DNMT3A p.Arg659Cys (c.1975C>T) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.1145); Very rare (popmax 0.00134%, afr).

How common is DNMT3A p.Arg659Cys (c.1975C>T) in the general population?

DNMT3A p.Arg659Cys (c.1975C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about DNMT3A p.Arg659Cys (c.1975C>T)?

AlphaMissense predicts likely benign (score 0.1145) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg659Cys

c.1975C>T · VCV3372719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1145	likely benign
REVEL	0.569	indeterminate
SaProt	LLR -13.61	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 1.7, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 4,806 bp · p 8.9e-10 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00134% African / African-American · 1/74,894 alleles

Overall 0.000124% 2/1,613,856 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	8.47e-05%	1,179,952

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.Arg659Cys
Coding: c.1975C>T
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25241669 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 659: a β-strand; the sam-dependent mtase c5-type domain

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

Similar variants

DNMT3A p.Arg659His Conflicting classifications of pathogenicity ★ ⚠ same residue
DNMT3A p.Arg659= Likely benign ★ same residue
DNMT3A p.Arg659fs Likely pathogenic ★ 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

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-arg659cys (accessed [today's date]).

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