Is DNMT3A c.1122+7G>A pathogenic?

DNMT3A c.1122+7G>A is classified Benign in DNMT3A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 75%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A c.1122+7G>A?

DNMT3A c.1122+7G>A is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

DNMT3A c.1122+7G>A

Q: How common is DNMT3A c.1122+7G>A in the general population?

DNMT3A c.1122+7G>A is common (popmax 75%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs2276599 · VCV1169864

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 75%, nfe) — 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
Splice region	donor +7	near-intronic (+7 nt from the splice site) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -2.4
Non-coding constraint	Z 5.64	1 kb window · o/e 0.66 · regional · uncalibrated
Overall
CADD	0.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 75% European (non-Finnish) · 884,313/1,179,258 alleles

Filtering AF 74.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 74.8%

Overall 72.7% 1,173,178/1,612,618 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	82%	1
European (non-Finnish)grpmax	75%	1
Admixed American	74%	1
Amishnot grpmax-eligible	72.7%	1
Remaining individualsnot grpmax-eligible	71.1%	1
Ashkenazi Jewishnot grpmax-eligible	67.9%	1
Middle Eastern	66.3%	2
South Asian	60.5%	2
East Asian	58%	2
African / African-American	56.1%	2

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.1122+7G>A
MANE Select: NM_022552
dbSNP: rs2276599
Type: single nucleotide variant
Location: chr2:25247044 (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-1122-plus-7g-a (accessed [today's date]).

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