Is DNMT3A p.Arg882His (c.2645G>A) pathogenic?

DNMT3A p.Arg882His (c.2645G>A) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9953); Ultra-rare (popmax 0.0454%, afr); Associated with congenital nervous system disorder.

What condition is associated with DNMT3A p.Arg882His (c.2645G>A)?

DNMT3A p.Arg882His (c.2645G>A) is associated with congenital nervous system disorder, intellectual disability, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Arg882His (c.2645G>A) in the general population?

DNMT3A p.Arg882His (c.2645G>A) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

What do computational predictors say about DNMT3A p.Arg882His (c.2645G>A)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg882His

c.2645G>A · rs147001633 · VCV375881

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital nervous system disorder

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic ✓ concordant with ClinVar
REVEL	0.742	pathogenic-leaning
SaProt	LLR -14.30	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 110 bp · p 0.5 · regional, not allelic
Overall
CADD	28.5	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 0.0454% African / African-American · 34/74,814 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.0265% 427/1,612,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,971
African / African-Americangrpmax	0.0454%	2,200
European (non-Finnish)	0.0268%	3,731
East Asian	0.0268%	3,737
Finnishnot grpmax-eligible	0.0219%	4,568
South Asian	0.0209%	4,790
Remaining individualsnot grpmax-eligible	0.0144%	6,938
Admixed American	0.0133%	7,493

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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Acute Myeloid Leukemia	Daunorubicin	B	Resistance
Acute Myeloid Leukemia		B	Negative
Acute Myeloid Leukemia		B	Positive
Acute Myeloid Leukemia		B	Better Outcome
Acute Myeloid Leukemia		B	Positive
Acute Myeloid Leukemia		B	Positive
Acute Myeloid Leukemia		B
Acute Myeloid Leukemia		B	Better Outcome

Variant & gene context

Gene: DNMT3A
Protein: p.Arg882His
Coding: c.2645G>A
MANE Select: NM_022552
dbSNP: rs147001633
Type: single nucleotide variant
Location: chr2:25234373 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 882: an α-helix; the sam-dependent mtase c5-type domain; a UniProt-annotated variant site (in tbrs and aml; somatic variant in aml); a UniProt-annotated variant site (in a patient with chronic myelomonocytic leukemia; somatic mutation)

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

Disease context

congenital nervous system disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability Tatton-Brown-Rahman overgrowth syndrome acute myeloid leukemia

Similar variants

DNMT3A p.Arg882Cys Pathogenic/Likely pathogenic ★★ same residue
DNMT3A p.Arg882Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
DNMT3A p.Arg882= Likely benign ★ 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

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-arg882his (accessed [today's date]).

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