Is DNMT3B p.Asp172= (c.516C>T) pathogenic?

DNMT3B p.Asp172= (c.516C>T) is classified Conflicting classifications of pathogenicity in DNMT3B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-16). Ultra-rare (popmax 0.0446%, eas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1.

What condition is associated with DNMT3B p.Asp172= (c.516C>T)?

DNMT3B p.Asp172= (c.516C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 1, immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Asp172= (c.516C>T) in the general population?

DNMT3B p.Asp172= (c.516C>T) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

DNMT3B p.Asp172=

c.516C>T · rs202113400 · VCV338156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 1

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 -3.9	GERP -3.5
Overall
CADD	2.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0446% East Asian · 20/44,882 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00409% 66/1,614,022 alleles · ultra-rare exomes 63/1,461,810 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
Middle Eastern	0.0164%	6,084
African / African-American	0.004%	24,980
European (non-Finnish)	0.00339%	29,499
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,096

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.Asp172=
Coding: c.516C>T
MANE Select: NM_006892
dbSNP: rs202113400
Type: single nucleotide variant
Location: chr20:32787313 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 172: 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 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-asp172 (accessed [today's date]).

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