DNMT3A p.Cys497=
c.1491T>C · rs375421208 · VCV434952
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0293%, afr)
Conditions
2
Inborn genetic diseases
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 2.8 | GERP -1.6, phastCons 1 |
| Overall | ||
| CADD | 7.676 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0293%
African / African-American · 22/75,052 alleles
Filtering AF
0.0198%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0167%
Overall
0.00167%
27/1,613,904 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0293% | 3,411 |
| Admixed American | 0.005% | 20,006 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,245 |
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
- DNMT3A
- Protein
- p.Cys497=
- Coding
- c.1491T>C
- MANE Select
- NM_022552
- dbSNP
- rs375421208
- Type
- single nucleotide variant
- Location
- chr2:25245316 (GRCh38)
- Gene constraint
- LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 73.97 · 47 PDB
- Residue 497
- the 'interaction with the prc2/eed-ezh2 complex' region; the add domain; a turn
Similar variants
- DNMT3A p.Cys497Ser Uncertain significance ★ ⚠ same residue
- DNMT3A p.Cys497Phe Likely pathogenic ★ same residue
- DNMT3A c.1667+1G>A Likely pathogenic ★★ same condition
- DNMT3A c.1937-2A>G Pathogenic ★★ same condition
- DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same condition
- DNMT3A c.2479-1G>A Likely pathogenic ★★ same condition
- DNMT3A p.Arg143Ter Pathogenic ★★ same condition
- DNMT3A p.Arg301Trp 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/dnmt3a-p-cys497 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown