Is DNMT3B p.Phe446Ser (c.1337T>C) pathogenic?

DNMT3B p.Phe446Ser (c.1337T>C) is classified Uncertain significance in DNMT3B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-19). AlphaMissense: likely benign (0.2943); Ultra-rare (popmax 0.0922%, sas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Phe446Ser (c.1337T>C)?

DNMT3B p.Phe446Ser (c.1337T>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ClinVar).

How common is DNMT3B p.Phe446Ser (c.1337T>C) in the general population?

DNMT3B p.Phe446Ser (c.1337T>C) is ultra-rare (popmax 0.0922%, sas) (gnomAD).

What do computational predictors say about DNMT3B p.Phe446Ser (c.1337T>C)?

AlphaMissense predicts likely benign (score 0.2943) — an in-silico prediction, not a clinical call.

DNMT3B p.Phe446Ser

c.1337T>C · rs150736372 · VCV800927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0922%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.2943	likely benign
REVEL	0.554	indeterminate
SaProt	LLR -3.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,534 bp · p 0.3 · regional, not allelic
Overall
CADD	22.6	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 0.0922% South Asian · 84/91,088 alleles

Filtering AF 0.0763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0704%

Overall 0.00737% 119/1,614,090 alleles · ultra-rare exomes 117/1,461,894 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0922%	1,084
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.005%	20,003
European (non-Finnish)	0.00186%	53,638

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.Phe446Ser
Coding: c.1337T>C
MANE Select: NM_006892
dbSNP: rs150736372
Type: single nucleotide variant
Location: chr20:32796829 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 446: the add domain; a β-strand; 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

Also linked: immunodeficiency-centromeric instability-facial anomalies syndrome 1

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-phe446ser (accessed [today's date]).

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