Is DNMT3B p.Asp627= (c.1881C>T) pathogenic?

DNMT3B p.Asp627= (c.1881C>T) is classified Benign in DNMT3B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 18.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1.

What condition is associated with DNMT3B p.Asp627= (c.1881C>T)?

DNMT3B p.Asp627= (c.1881C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1, immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

DNMT3B p.Asp627=

Q: How common is DNMT3B p.Asp627= (c.1881C>T) in the general population?

DNMT3B p.Asp627= (c.1881C>T) is common (popmax 18.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1881C>T · rs17123657 · VCV338179

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 18.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	donor gain · deltas
Pangolin	Δ0.20	gain · loss 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -8.6	GERP -4.2
Overall
CADD	13.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.3% African / African-American · 13,714/74,962 alleles

Filtering AF 18% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.9%

Overall 1.19% 19,287/1,614,076 alleles · common exomes 11,064/1,461,884 · genomes 8,223/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.3%	5
Middle Eastern	6.6%	15
Remaining individualsnot grpmax-eligible	2.05%	49
Admixed American	1.92%	52
Ashkenazi Jewishnot grpmax-eligible	1.15%	87
European (non-Finnish)	0.193%	518
South Asian	0.128%	778
East Asian	0.00223%	44,886
Finnishnot grpmax-eligible	0.00156%	64,018

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.Asp627=
Coding: c.1881C>T
MANE Select: NM_006892
dbSNP: rs17123657
Type: single nucleotide variant
Location: chr20:32800274 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 627: a binding site; the sam-dependent mtase c5-type domain

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

Also linked: immunodeficiency-centromeric instability-facial anomalies syndrome

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-asp627 (accessed [today's date]).

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