Is DNMT3B p.Arg97Cys (c.289C>T) pathogenic?

DNMT3B p.Arg97Cys (c.289C>T) is classified Uncertain significance in DNMT3B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: likely benign (0.1329); Very rare (popmax 0.00549%, sas); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Arg97Cys (c.289C>T)?

DNMT3B p.Arg97Cys (c.289C>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Arg97Cys (c.289C>T) in the general population?

DNMT3B p.Arg97Cys (c.289C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about DNMT3B p.Arg97Cys (c.289C>T)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

DNMT3B p.Arg97Cys

c.289C>T · rs769220144 · VCV1512131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.39	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP -0.01
Regional constraint	o/e 0.94	unconstrained · MANE · 8,530 bp · p 0.27 · regional, not allelic
Overall
CADD	22.5	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 0.00549% South Asian · 5/91,076 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.0044% 71/1,613,962 alleles · very rare exomes 67/1,461,870 · genomes 4/152,092 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
European (non-Finnish)	0.00534%	18,731
African / African-American	0.00267%	37,438
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg97Cys
Coding: c.289C>T
MANE Select: NM_006892
dbSNP: rs769220144
Type: single nucleotide variant
Location: chr20:32784842 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 97: 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.Arg97His Uncertain significance ★★ ⚠ same residue
DNMT3B p.Arg97Gly 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-arg97cys (accessed [today's date]).

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