Is DNMT3A p.Val716Ile (c.2146G>A) pathogenic?

DNMT3A p.Val716Ile (c.2146G>A) is classified Pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-06). AlphaMissense: likely pathogenic (0.9594); Very rare (popmax 0.000678%, nfe).

How common is DNMT3A p.Val716Ile (c.2146G>A) in the general population?

DNMT3A p.Val716Ile (c.2146G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Val716Ile (c.2146G>A)?

AlphaMissense predicts likely pathogenic (score 0.9594) — an in-silico prediction, not a clinical call.

DNMT3A p.Val716Ile

c.2146G>A · rs1418039680 · VCV977200

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9594	likely pathogenic ✓ concordant with ClinVar
REVEL	0.59	indeterminate
SaProt	LLR -11.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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	25.7	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 0.000678% European (non-Finnish) · 8/1,180,040 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000616% 9/1,461,866 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,032
European (non-Finnish)grpmax	0.000678%	147,505

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
Protein: p.Val716Ile
Coding: c.2146G>A
MANE Select: NM_022552
dbSNP: rs1418039680
Type: single nucleotide variant
Location: chr2:25240667 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 716: a β-strand; the sam-dependent mtase c5-type domain

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-p-val716ile (accessed [today's date]).

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