Is DNMT3A p.Val372Ile (c.1114G>A) pathogenic?

DNMT3A p.Val372Ile (c.1114G>A) is classified Uncertain significance in DNMT3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.3844); Very rare (popmax 0.0039%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Val372Ile (c.1114G>A)?

DNMT3A p.Val372Ile (c.1114G>A) is associated with Inborn genetic diseases, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Val372Ile (c.1114G>A) in the general population?

DNMT3A p.Val372Ile (c.1114G>A) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Val372Ile (c.1114G>A)?

AlphaMissense predicts ambiguous (score 0.3844) — an in-silico prediction, not a clinical call.

DNMT3A p.Val372Ile

c.1114G>A · rs371677904 · VCV2076359

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3844	ambiguous
REVEL	0.128	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.26, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	24.4	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 0.0039% European (non-Finnish) · 46/1,179,930 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00291% 47/1,613,882 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,651
Admixed American	0.00167%	59,984

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.Val372Ile
Coding: c.1114G>A
MANE Select: NM_022552
dbSNP: rs371677904
Type: single nucleotide variant
Location: chr2:25247059 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 372: the 'interaction with dnmt1 and dnmt3b' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tatton-Brown-Rahman overgrowth syndrome

Similar variants

DNMT3A p.Val372= Likely benign ★★ same residue
DNMT3A p.Val372Gly Uncertain significance ★ ⚠ 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.Arg301Trp 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-val372ile (accessed [today's date]).

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