DOT1L p.Lys358=
c.1074G>A · VCV4872125
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0817%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.218 | benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.8 | GERP -2.4, phastCons 1 |
| Overall | ||
| CADD | 2.014 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0817%
European (non-Finnish) · 957/1,171,278 alleles
Filtering AF
0.0774%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0756%
Overall
0.0666%
1,059/1,590,658 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0817% | 1,224 |
| Remaining individualsnot grpmax-eligible | 0.052% | 1,923 |
| Admixed American | 0.0421% | 2,378 |
| Finnishnot grpmax-eligible | 0.0386% | 2,589 |
| Middle Eastern | 0.0381% | 2,623 |
| African / African-American | 0.0295% | 3,388 |
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
- DOT1L
- Protein
- p.Lys358=
- Coding
- c.1074G>A
- MANE Select
- NM_032482
- Type
- single nucleotide variant
- Location
- chr19:2210468 (GRCh38)
- Gene constraint
- LOEUF 0.321 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 54.11 · 48 PDB
- Residue 358
- the 'disordered' region; the 'required for dna binding and full methyltransferase activity' region
Similar variants
- DOT1L p.Lys358Glu Uncertain significance ★ same residue
- DOT1L p.Asp189Asn Uncertain significance ★★ ⚠ same type
- DOT1L p.Ala1101= Benign ★★ same type
- DOT1L p.Arg73= Benign ★★ same type
- DOT1L p.Arg893= Benign/Likely benign ★★ same type
- DOT1L p.Asp155= Benign ★★ same type
- DOT1L p.Pro758= Likely benign ★★ same type
- DOT1L p.Thr1068= Benign/Likely benign ★★ same type
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/dot1l-p-lys358 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown