Is DNMT3B p.Pro159Ser (c.475C>T) pathogenic?

DNMT3B p.Pro159Ser (c.475C>T) is classified Uncertain significance in DNMT3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0681); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNMT3B p.Pro159Ser (c.475C>T)?

DNMT3B p.Pro159Ser (c.475C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT3B p.Pro159Ser (c.475C>T) in the general population?

DNMT3B p.Pro159Ser (c.475C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about DNMT3B p.Pro159Ser (c.475C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

DNMT3B p.Pro159Ser

c.475C>T · VCV4243647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -5.16	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 -1.3	GERP -3.8
Regional constraint	o/e 0.94	unconstrained · MANE · 8,530 bp · p 0.27 · regional, not allelic
Overall
CADD	0.123	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 0.004% African / African-American · 3/74,944 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,118 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,981
European (non-Finnish)	8.47e-05%	1,180,057

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.Pro159Ser
Coding: c.475C>T
MANE Select: NM_006892
Type: single nucleotide variant
Location: chr20:32787272 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 159: the 'interaction with dnmt1 and dnmt3a' region; the 'disordered' region

Full DNMT3B 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

Similar variants

DNMT3B p.Pro159Gln Uncertain significance ★ ⚠ same residue
DNMT3B p.Pro159= Likely benign ★ same residue
DNMT3B p.Ala569Thr Uncertain significance ★★ ⚠ same condition
DNMT3B p.Arg122His Uncertain significance ★★ ⚠ same condition
DNMT3B p.Arg148Trp Uncertain significance ★★ ⚠ same condition
DNMT3B p.Arg149Gln Uncertain significance ★★ ⚠ same condition
DNMT3B p.Arg190Cys Uncertain significance ★★ ⚠ same condition
DNMT3B p.Arg459Gln Uncertain significance ★★ ⚠ 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-pro159ser (accessed [today's date]).

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