Is DNMT3B p.Val296Ile (c.886G>A) pathogenic?

DNMT3B p.Val296Ile (c.886G>A) is classified Conflicting classifications of pathogenicity in DNMT3B (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1305); Rare (popmax 0.207%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Val296Ile (c.886G>A)?

DNMT3B p.Val296Ile (c.886G>A) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1, facioscapulohumeral muscular dystrophy 4, digenic (ClinVar).

How common is DNMT3B p.Val296Ile (c.886G>A) in the general population?

DNMT3B p.Val296Ile (c.886G>A) is rare (popmax 0.207%, afr) (gnomAD).

What do computational predictors say about DNMT3B p.Val296Ile (c.886G>A)?

AlphaMissense predicts likely benign (score 0.1305) — an in-silico prediction, not a clinical call.

DNMT3B p.Val296Ile

c.886G>A · rs145632647 · VCV423264

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1305 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.207%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.1305	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,534 bp · p 0.3 · regional, not allelic
Overall
CADD	22.9	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 0.207% African / African-American · 155/75,022 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0354% 571/1,614,096 alleles · rare exomes 442/1,461,798 · genomes 129/152,298 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.797%	125
African / African-Americangrpmax	0.207%	484
Remaining individualsnot grpmax-eligible	0.0688%	1,454
Admixed American	0.0167%	6,002
East Asian	0.0111%	8,975
European (non-Finnish)	0.00975%	10,261
South Asian	0.00768%	13,013

Ashkenazi Jewish 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: DNMT3B
Protein: p.Val296Ile
Coding: c.886G>A
MANE Select: NM_006892
dbSNP: rs145632647
Type: single nucleotide variant
Location: chr20:32791673 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 296: the 'interaction with dnmt1 and dnmt3a' region; an α-helix

Full DNMT3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency-centromeric instability-facial anomalies syndrome 1 facioscapulohumeral muscular dystrophy 4, digenic

Similar variants

DNMT3B c.2421-11G>A Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Ala603Thr Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Arg826Cys Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Arg840Gln Likely pathogenic ★★ same condition
DNMT3B p.Asp653Asn Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.His814Arg Likely pathogenic ★★ ⚠ same condition
DNMT3B p.Val613Ala Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Val726Gly 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/dnmt3b-p-val296ile (accessed [today's date]).

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