Is DNMT3A p.Pro904Ser (c.2710C>T) pathogenic?

DNMT3A p.Pro904Ser (c.2710C>T) is classified Likely pathogenic in DNMT3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-11). AlphaMissense: likely pathogenic (0.989); Very rare (popmax 8.47e-05%, nfe); Associated with glioblastoma.

What condition is associated with DNMT3A p.Pro904Ser (c.2710C>T)?

DNMT3A p.Pro904Ser (c.2710C>T) is associated with glioblastoma (ClinVar).

How common is DNMT3A p.Pro904Ser (c.2710C>T) in the general population?

DNMT3A p.Pro904Ser (c.2710C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Glioblastoma inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DNMT3A p.Pro904Ser (c.2710C>T)?

AlphaMissense predicts likely pathogenic (score 0.989) — an in-silico prediction, not a clinical call.

DNMT3A p.Pro904Ser

c.2710C>T · rs1558650888 · VCV635110

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glioblastoma

Computational evidence

Protein change
AlphaMissense	0.989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -14.41	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 110 bp · p 0.5 · regional, not allelic
Overall
CADD	28.6	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 8.47e-05% European (non-Finnish) · 1/1,179,964 alleles

Overall 0.000124% 2/1,613,892 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)grpmax	8.47e-05%	1,179,965

Finnish 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.

Variant & gene context

Gene: DNMT3A
Protein: p.Pro904Ser
Coding: c.2710C>T
MANE Select: NM_022552
dbSNP: rs1558650888
Type: single nucleotide variant
Location: chr2:25234308 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 904: an α-helix; the sam-dependent mtase c5-type domain; a UniProt-annotated variant site (in tbrs; somatic mutation)

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

Disease context

glioblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glioblastoma (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

DNMT3A p.Pro904Leu Pathogenic/Likely pathogenic ★★ same residue
DNMT3A p.Pro904= Likely benign ★ 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

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-pro904ser (accessed [today's date]).

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