Is DNMT3A c.640-1663G>A pathogenic?

DNMT3A c.640-1663G>A is classified Benign in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-06). Common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele.

DNMT3A c.640-1663G>A

Q: How common is DNMT3A c.640-1663G>A in the general population?

DNMT3A c.640-1663G>A is common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs11681447 · VCV1296240

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	acceptor -1663	deep intronic (-1663 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -2.1
Non-coding constraint	Z 3.75	1 kb window · o/e 0.74 · regional · uncalibrated
Overall
CADD	6.408	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 75.2% European (non-Finnish) · 51,086/67,966 alleles

Filtering AF 74.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 74.4%

Overall 67.8% 103,083/152,012 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	82%	1
European (non-Finnish)grpmax	75.2%	1
Amishnot grpmax-eligible	72.8%	1
Admixed American	71.6%	1
Remaining individualsnot grpmax-eligible	67.7%	1
Ashkenazi Jewishnot grpmax-eligible	67.2%	1
Middle Eastern	65%	2
East Asian	60.1%	2
South Asian	59%	2
African / African-American	52.7%	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.640-1663G>A
MANE Select: NM_022552
dbSNP: rs11681447
Type: single nucleotide variant
Location: chr2:25249915 (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

Similar variants

DNMT3A c.1667+1G>A Likely pathogenic ★★ same type
DNMT3A c.1937-2A>G Pathogenic ★★ same type
DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same type
DNMT3A c.2479-1G>A Likely pathogenic ★★ same type
DNMT3A p.Arg143Ter Pathogenic ★★ same type
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Arg598Ter Pathogenic/Likely pathogenic ★★ same type

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-640-minus-1663g-a (accessed [today's date]).

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