Is DNMT3A p.Trp330Arg (c.988T>C) pathogenic?

DNMT3A p.Trp330Arg (c.988T>C) is classified Pathogenic in DNMT3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-02). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with Heyn-Sproul-Jackson syndrome.

What condition is associated with DNMT3A p.Trp330Arg (c.988T>C)?

DNMT3A p.Trp330Arg (c.988T>C) is associated with Heyn-Sproul-Jackson syndrome (ClinVar).

How common is DNMT3A p.Trp330Arg (c.988T>C) in the general population?

DNMT3A p.Trp330Arg (c.988T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Trp330Arg (c.988T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

DNMT3A p.Trp330Arg

c.988T>C · rs1573340475 · VCV801331

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Heyn-Sproul-Jackson syndrome

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 7% in DNMT3A
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -14.07	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT3A
Protein: p.Trp330Arg
Coding: c.988T>C
MANE Select: NM_022552
dbSNP: rs1573340475
Type: single nucleotide variant
Location: chr2:25247617 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 330: the pwwp domain; a UniProt-annotated variant site (in hesjas; no effect on protein expression; changed dna methylation; results in aberrant expression of genes involved in developmental processes); a β-strand; the 'interaction with dnmt1 and dnmt3b' region

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

Disease context

Heyn-Sproul-Jackson syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A p.Trp330Leu Likely pathogenic ★ same residue
DNMT3A p.Arg771Gln Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg882Cys Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Trp601Ter Pathogenic ★★ same condition
DNMT3A p.Tyr660His Likely pathogenic ★★ same condition
DNMT3A p.Arg96Gln Uncertain significance ★★ ⚠ same condition
DNMT3A p.Cys911Tyr Uncertain significance ★★ ⚠ same condition
DNMT3A p.Lys219Arg 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-trp330arg (accessed [today's date]).

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