Is DNMT3A p.Val687Ile (c.2059G>A) pathogenic?

DNMT3A p.Val687Ile (c.2059G>A) is classified Uncertain significance in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-03). AlphaMissense: likely benign (0.1624); Very rare (popmax 0.0011%, sas); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Val687Ile (c.2059G>A)?

DNMT3A p.Val687Ile (c.2059G>A) is associated with Tatton-Brown-Rahman overgrowth syndrome, Heyn-Sproul-Jackson syndrome (ClinVar).

How common is DNMT3A p.Val687Ile (c.2059G>A) in the general population?

DNMT3A p.Val687Ile (c.2059G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DNMT3A p.Val687Ile (c.2059G>A)?

AlphaMissense predicts likely benign (score 0.1624) — an in-silico prediction, not a clinical call.

DNMT3A p.Val687Ile

c.2059G>A · rs1183198167 · VCV1339120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.1624	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -11.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 4,806 bp · p 8.9e-10 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,054 alleles

Overall 0.000124% 2/1,613,854 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,054
European (non-Finnish)	8.47e-05%	1,179,947

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.Val687Ile
Coding: c.2059G>A
MANE Select: NM_022552
dbSNP: rs1183198167
Type: single nucleotide variant
Location: chr2:25241585 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 687: an α-helix; a binding site; the sam-dependent mtase c5-type domain

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

Also linked: Heyn-Sproul-Jackson syndrome

Similar variants

DNMT3A p.Val687= Likely benign ★ 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
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter 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-val687ile (accessed [today's date]).

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