Is DNMT3A p.Pro59= (c.177G>A) pathogenic?

DNMT3A p.Pro59= (c.177G>A) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). Very rare (popmax 0.00017%, nfe); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Pro59= (c.177G>A)?

DNMT3A p.Pro59= (c.177G>A) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Pro59= (c.177G>A) in the general population?

DNMT3A p.Pro59= (c.177G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

DNMT3A p.Pro59=

c.177G>A · VCV3699548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Pangolin	Δ0.32	gain · loss 0.17 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 0.51, phastCons 1
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,686 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,840 alleles · very rare

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.Pro59=
Coding: c.177G>A
MANE Select: NM_022552
Type: single nucleotide variant
Location: chr2:25300139 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 59: the 'disordered' region

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 p.Pro59Gln Uncertain significance ★ ⚠ same residue
DNMT3A p.Pro59Leu Uncertain significance ★ ⚠ same residue
DNMT3A p.Pro59Ser Uncertain significance ★ ⚠ same residue
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

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-pro59 (accessed [today's date]).

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