Is DNMT3A p.Arg301Trp (c.901C>T) pathogenic?

DNMT3A p.Arg301Trp (c.901C>T) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.9958); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Arg301Trp (c.901C>T)?

DNMT3A p.Arg301Trp (c.901C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT3A p.Arg301Trp (c.901C>T) in the general population?

DNMT3A p.Arg301Trp (c.901C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about DNMT3A p.Arg301Trp (c.901C>T)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg301Trp

c.901C>T · rs1553414070 · VCV432039

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic ✓ concordant with ClinVar
REVEL	0.69	pathogenic-leaning
SaProt	LLR -12.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 65 bp · p 0.008 · regional, not allelic
Overall
CADD	33.0	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 · 1/74,850 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,332 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,850
South Asian	0.0011%	91,038
European (non-Finnish)	0.000254%	393,306

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.Arg301Trp
Coding: c.901C>T
MANE Select: NM_022552
dbSNP: rs1553414070
Type: single nucleotide variant
Location: chr2:25247704 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 301: the pwwp domain; the 'interaction with dnmt1 and dnmt3b' region

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.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
DNMT3A p.Arg596Gln Uncertain significance ★★ ⚠ same condition
DNMT3A p.Asn489His 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-arg301trp (accessed [today's date]).

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