Is DNMT3B p.Pro396Ser (c.1186C>T) pathogenic?

DNMT3B p.Pro396Ser (c.1186C>T) is classified Uncertain significance in DNMT3B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0868); Ultra-rare (popmax 0.0613%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Pro396Ser (c.1186C>T)?

DNMT3B p.Pro396Ser (c.1186C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Pro396Ser (c.1186C>T) in the general population?

DNMT3B p.Pro396Ser (c.1186C>T) is ultra-rare (popmax 0.0613%, afr) (gnomAD).

What do computational predictors say about DNMT3B p.Pro396Ser (c.1186C>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

DNMT3B p.Pro396Ser

c.1186C>T · rs138171867 · VCV948251

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.24	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 -0.19	GERP -1.6
Regional constraint	o/e 0.93	unconstrained · MANE · 5,534 bp · p 0.3 · regional, not allelic
Overall
CADD	7.043	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 0.0613% African / African-American · 46/75,050 alleles

Filtering AF 0.0471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0422%

Overall 0.00415% 67/1,614,198 alleles · ultra-rare exomes 44/1,461,890 · genomes 23/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0613%	1,632
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0256%	3,907
Admixed American	0.00333%	30,009
European (non-Finnish)	8.47e-05%	1,180,036

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.Pro396Ser
Coding: c.1186C>T
MANE Select: NM_006892
dbSNP: rs138171867
Type: single nucleotide variant
Location: chr20:32795468 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 396: the 'disordered' 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 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-pro396ser (accessed [today's date]).

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