Is DOT1L p.Cys75= (c.225C>T) pathogenic?

DOT1L p.Cys75= (c.225C>T) is classified Likely benign in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). Ultra-rare (popmax 0.0733%, afr); Associated with Inborn genetic diseases.

What condition is associated with DOT1L p.Cys75= (c.225C>T)?

DOT1L p.Cys75= (c.225C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DOT1L p.Cys75= (c.225C>T) in the general population?

DOT1L p.Cys75= (c.225C>T) is ultra-rare (popmax 0.0733%, afr) (gnomAD).

DOT1L p.Cys75=

c.225C>T · VCV3842179

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, afr)

Conditions

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 -0.004	GERP -2.2, phastCons 0.95
Overall
CADD	10.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0733% African / African-American · 55/75,054 alleles

Filtering AF 0.0578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0522%

Overall 0.00813% 131/1,611,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0733%	1,365
South Asian	0.0406%	2,462
Remaining individualsnot grpmax-eligible	0.0096%	10,414
East Asian	0.00891%	11,222
Admixed American	0.00666%	15,008
European (non-Finnish)	0.00203%	49,166
Finnishnot grpmax-eligible	0.00162%	61,790

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.Cys75=
Coding: c.225C>T
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2189756 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB
Residue 75: the dot1 domain; an α-helix

Full DOT1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOT1L p.Thr957Ile Likely benign ★★ same condition
DOT1L p.Ala1003Pro Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1053Val Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1071Thr Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1094Val Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1230Val Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1303Gly Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1364Pro Uncertain significance ★ ⚠ 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/dot1l-p-cys75 (accessed [today's date]).

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