Is DNMT3B p.Ala14= (c.42C>T) pathogenic?

DNMT3B p.Ala14= (c.42C>T) is classified Benign/Likely benign in DNMT3B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-21). Rare (popmax 0.468%, eas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Ala14= (c.42C>T)?

DNMT3B p.Ala14= (c.42C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ClinVar).

How common is DNMT3B p.Ala14= (c.42C>T) in the general population?

DNMT3B p.Ala14= (c.42C>T) is rare (popmax 0.468%, eas) (gnomAD).

DNMT3B p.Ala14=

c.42C>T · rs730823 · VCV530709

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.468%, eas)

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.67, phastCons 1
Overall
CADD	15.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.468% East Asian · 210/44,864 alleles

Filtering AF 0.416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.396%

Overall 0.0226% 365/1,613,918 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.468%	214
Remaining individualsnot grpmax-eligible	0.16%	625
African / African-American	0.0267%	3,749
South Asian	0.0209%	4,793
Admixed American	0.00333%	30,000
European (non-Finnish)	0.00119%	84,286

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.Ala14=
Coding: c.42C>T
MANE Select: NM_006892
dbSNP: rs730823
Type: single nucleotide variant
Location: chr20:32780365 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 14: 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

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

Similar variants

DNMT3B p.Ala14Pro 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
DNMT3B p.Val613Ala 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-ala14 (accessed [today's date]).

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