Is DNMT3A p.Pro9= (c.27C>T) pathogenic?

DNMT3A p.Pro9= (c.27C>T) is classified Benign/Likely benign in DNMT3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 16.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Pro9= (c.27C>T)?

DNMT3A p.Pro9= (c.27C>T) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

DNMT3A p.Pro9=

Q: How common is DNMT3A p.Pro9= (c.27C>T) in the general population?

DNMT3A p.Pro9= (c.27C>T) is common (popmax 16.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.27C>T · rs41284843 · VCV1169865

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 16.9%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP 0.53, phastCons 0.87
Overall
CADD	13.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.9% South Asian · 14,169/83,812 alleles

Filtering AF 16.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.6%

Overall 9.81% 151,926/1,549,098 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	16.9%	6
Amishnot grpmax-eligible	13.4%	7
East Asian	10.2%	10
Ashkenazi Jewishnot grpmax-eligible	10.2%	10
Middle Eastern	10%	10
European (non-Finnish)	9.85%	10
Remaining individualsnot grpmax-eligible	9.77%	10
Finnishnot grpmax-eligible	6.47%	15
Admixed American	6.05%	17
African / African-American	6%	17

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.Pro9=
Coding: c.27C>T
MANE Select: NM_022552
dbSNP: rs41284843
Type: single nucleotide variant
Location: chr2:25313958 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 9: 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 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-pro9 (accessed [today's date]).

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