Is DNMT3A p.Trp860Ter (c.2580G>A) pathogenic?

DNMT3A p.Trp860Ter (c.2580G>A) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-08). Very rare (popmax 0.004%, afr); Associated with intellectual disability.

What condition is associated with DNMT3A p.Trp860Ter (c.2580G>A)?

DNMT3A p.Trp860Ter (c.2580G>A) is associated with intellectual disability (ClinVar).

How common is DNMT3A p.Trp860Ter (c.2580G>A) in the general population?

DNMT3A p.Trp860Ter (c.2580G>A) is very rare (popmax 0.004%, afr) (gnomAD).

DNMT3A p.Trp860Ter

c.2580G>A · rs376830288 · VCV2606701

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (22 of 23, 17 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.81, phastCons 1
Overall
CADD	44.0	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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,613,894 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
European (non-Finnish)	0.000339%	294,978

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.Trp860Ter
Coding: c.2580G>A
MANE Select: NM_022552
dbSNP: rs376830288
Type: single nucleotide variant
Location: chr2:25235724 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 860: an α-helix; the sam-dependent mtase c5-type domain

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3A p.Arg143Ter Pathogenic ★★ same condition
DNMT3A p.Arg882His Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Tyr908Asn Likely pathogenic ★ same condition
DNMT3A p.Arg19Gln Uncertain significance ★ ⚠ same condition
DNMT3A p.Arg736Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
DNMT3A p.Gly332Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
DNMT3A p.Glu235fs Likely pathogenic ★ same condition
DNMT3A c.1667+1G>A 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-p-trp860ter (accessed [today's date]).

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