Is DNMT3B p.Pro44Leu (c.131C>T) pathogenic?

DNMT3B p.Pro44Leu (c.131C>T) is classified Uncertain significance in DNMT3B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely benign (0.1432); Very rare (popmax 0.00669%, eas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Pro44Leu (c.131C>T)?

DNMT3B p.Pro44Leu (c.131C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Pro44Leu (c.131C>T) in the general population?

DNMT3B p.Pro44Leu (c.131C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about DNMT3B p.Pro44Leu (c.131C>T)?

AlphaMissense predicts likely benign (score 0.1432) — an in-silico prediction, not a clinical call.

DNMT3B p.Pro44Leu

c.131C>T · rs781313570 · VCV1366987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.1432	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.81, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 8,530 bp · p 0.27 · regional, not allelic
Overall
CADD	21.1	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 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000558% 9/1,612,968 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
South Asian	0.0011%	91,052
European (non-Finnish)	0.000424%	235,994

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.Pro44Leu
Coding: c.131C>T
MANE Select: NM_006892
dbSNP: rs781313570
Type: single nucleotide variant
Location: chr20:32780454 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 44: 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

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

Similar variants

DNMT3B p.Pro44= Conflicting classifications of pathogenicity ★ same residue
DNMT3B p.Pro44Ser Uncertain significance ★ ⚠ 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-pro44leu (accessed [today's date]).

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