Is DNMT3A c.2408+2T>C pathogenic?

DNMT3A c.2408+2T>C is classified Likely pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). Very rare (popmax 0.00223%, eas); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A c.2408+2T>C?

DNMT3A c.2408+2T>C is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A c.2408+2T>C in the general population?

DNMT3A c.2408+2T>C is very rare (popmax 0.00223%, eas) (gnomAD).

DNMT3A c.2408+2T>C

VCV3383961

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.94	donor loss · deltas
Pangolin	Δ0.84	loss · gain 0.49 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 0.57, phastCons 1
Non-coding constraint	Z 3.60	1 kb window · o/e 0.77 · regional · uncalibrated
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Overall 0.000186% 3/1,613,482 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
South Asian	0.0011%	91,058
European (non-Finnish)	8.48e-05%	1,179,750

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
Coding: c.2408+2T>C
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25239128 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB

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

Disease context

Tatton-Brown-Rahman overgrowth syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-c-2408-plus-2t-c (accessed [today's date]).

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