Is DNMT3A p.Ile490Thr (c.1469T>C) pathogenic?

DNMT3A p.Ile490Thr (c.1469T>C) is classified Uncertain significance in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-30). AlphaMissense: likely pathogenic (0.8058); Absent from gnomAD v4.1; Associated with DNMT3A-related disorder.

What condition is associated with DNMT3A p.Ile490Thr (c.1469T>C)?

DNMT3A p.Ile490Thr (c.1469T>C) is associated with DNMT3A-related disorder, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Ile490Thr (c.1469T>C) in the general population?

DNMT3A p.Ile490Thr (c.1469T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Ile490Thr (c.1469T>C)?

AlphaMissense predicts likely pathogenic (score 0.8058) — an in-silico prediction, not a clinical call.

DNMT3A p.Ile490Thr

c.1469T>C · rs757283738 · VCV2636114

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8058 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DNMT3A-related disorder

Computational evidence

Protein change
AlphaMissense	0.8058	likely pathogenic
REVEL	0.327	indeterminate
SaProt	LLR -14.72	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	26.1	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

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.Ile490Thr
Coding: c.1469T>C
MANE Select: NM_022552
dbSNP: rs757283738
Type: single nucleotide variant
Location: chr2:25246025 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 490: the add domain; an α-helix

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

Disease context

DNMT3A-related disorder

Also linked: Tatton-Brown-Rahman overgrowth syndrome

Similar variants

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
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg688His Pathogenic/Likely 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-ile490thr (accessed [today's date]).

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