Is DNMT3B p.Pro443Ala (c.1327C>G) pathogenic?

DNMT3B p.Pro443Ala (c.1327C>G) is classified Uncertain significance in DNMT3B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely benign (0.0971); Very rare (popmax 8.47e-05%, nfe); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Pro443Ala (c.1327C>G)?

DNMT3B p.Pro443Ala (c.1327C>G) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Pro443Ala (c.1327C>G) in the general population?

DNMT3B p.Pro443Ala (c.1327C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DNMT3B p.Pro443Ala (c.1327C>G)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

DNMT3B p.Pro443Ala

c.1327C>G · rs752929250 · VCV1491996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.65	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 2.7	GERP -1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,534 bp · p 0.3 · regional, not allelic
Overall
CADD	14.11	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 0.000657% 1/152,192 alleles · very rare

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.Pro443Ala
Coding: c.1327C>G
MANE Select: NM_006892
dbSNP: rs752929250
Type: single nucleotide variant
Location: chr20:32796819 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 443: the add domain; the 'interaction with the prc2/eed-ezh2 complex' region

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

Similar variants

DNMT3B p.Pro443Leu Uncertain significance ★★ ⚠ same residue
DNMT3B p.Pro443= Likely benign ★ same residue
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

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-pro443ala (accessed [today's date]).

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