Is DOT1L p.Arg409Cys (c.1225C>T) pathogenic?

DOT1L p.Arg409Cys (c.1225C>T) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.7512); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOT1L p.Arg409Cys (c.1225C>T)?

DOT1L p.Arg409Cys (c.1225C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DOT1L p.Arg409Cys (c.1225C>T) in the general population?

DOT1L p.Arg409Cys (c.1225C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about DOT1L p.Arg409Cys (c.1225C>T)?

AlphaMissense predicts likely pathogenic (score 0.7512) — an in-silico prediction, not a clinical call.

DOT1L p.Arg409Cys

c.1225C>T · VCV4244329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7512	likely pathogenic
REVEL	0.256	benign-leaning
SaProt	LLR -10.40	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 758 bp · p 0.9 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,014 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,030 alleles · very rare

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.Arg409Cys
Coding: c.1225C>T
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2210729 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB
Residue 409: the 'disordered' region; the 'required for dna binding and full methyltransferase activity' region; the 'required for interaction with nucleosomes and dna' region

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-arg409cys (accessed [today's date]).

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