Is DNMT3A p.Arg631Ser (c.1893G>T) pathogenic?

DNMT3A p.Arg631Ser (c.1893G>T) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 8.72e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Arg631Ser (c.1893G>T)?

DNMT3A p.Arg631Ser (c.1893G>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT3A p.Arg631Ser (c.1893G>T) in the general population?

DNMT3A p.Arg631Ser (c.1893G>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Arg631Ser (c.1893G>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg631Ser

c.1893G>T · VCV3841803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 7% in DNMT3A
REVEL	0.353	indeterminate
SaProt	LLR -16.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.8, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 247 bp · p 6.8e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.72e-05% European (non-Finnish) · 1/1,147,356 alleles

Overall 7.14e-05% 1/1,400,342 alleles · very rare

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.Arg631Ser
Coding: c.1893G>T
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25243941 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 631: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A p.Arg631= Likely benign ★ same residue
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg688His Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Met548Thr Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Pro904Leu Pathogenic/Likely pathogenic ★★ same condition
DNMT3A c.448+48C>G Uncertain significance ★★ same condition
DNMT3A p.Arg544His Uncertain significance ★★ ⚠ 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-arg631ser (accessed [today's date]).

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