Is DNMT3A p.Ile705Ser (c.2114T>G) pathogenic?

DNMT3A p.Ile705Ser (c.2114T>G) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely pathogenic (0.9966); Absent from gnomAD v4.1.

How common is DNMT3A p.Ile705Ser (c.2114T>G) in the general population?

DNMT3A p.Ile705Ser (c.2114T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3A p.Ile705Ser (c.2114T>G)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

DNMT3A p.Ile705Ser

c.2114T>G · rs777037011 · VCV2663162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,030)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -16.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Constraint at this position
Conservation	phyloP 11	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	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,614,030). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DNMT3A
Protein: p.Ile705Ser
Coding: c.2114T>G
MANE Select: NM_022552
dbSNP: rs777037011
Type: single nucleotide variant
Location: chr2:25240699 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 705: 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 p.Ile705= Likely benign ★★ same residue
DNMT3A p.Ile705Met Uncertain significance ★ ⚠ same residue
DNMT3A p.Ile705Thr Uncertain significance ★ ⚠ same residue
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

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-ile705ser (accessed [today's date]).

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