Is DNMT3B p.Ser270Pro (c.808T>C) pathogenic?

DNMT3B p.Ser270Pro (c.808T>C) is classified Pathogenic in DNMT3B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-09-15). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1.

What condition is associated with DNMT3B p.Ser270Pro (c.808T>C)?

DNMT3B p.Ser270Pro (c.808T>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ClinVar).

How common is DNMT3B p.Ser270Pro (c.808T>C) in the general population?

DNMT3B p.Ser270Pro (c.808T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3B p.Ser270Pro (c.808T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

DNMT3B p.Ser270Pro

c.808T>C · rs121908947 · VCV6745

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 7% in DNMT3B
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -11.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 2,799 bp · p 2.8e-05 · regional, not allelic
Overall
CADD	29.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT3B
Protein: p.Ser270Pro
Coding: c.808T>C
MANE Select: NM_006892
dbSNP: rs121908947
Type: single nucleotide variant
Location: chr20:32789007 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 270: the pwwp domain; a UniProt-annotated variant site (in icf1); the 'interaction with dnmt1 and dnmt3a' region; a β-strand

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

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3B p.Ser270= 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.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-ser270pro (accessed [today's date]).

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