Is DOT1L p.Asp744Glu (c.2232C>G) pathogenic?

DOT1L p.Asp744Glu (c.2232C>G) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely benign (0.1607); Absent from gnomAD v4.1.

How common is DOT1L p.Asp744Glu (c.2232C>G) in the general population?

DOT1L p.Asp744Glu (c.2232C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOT1L p.Asp744Glu (c.2232C>G)?

AlphaMissense predicts likely benign (score 0.1607) — an in-silico prediction, not a clinical call.

DOT1L p.Asp744Glu

c.2232C>G · VCV3393588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1607 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1607	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,436 bp · p 0.28 · regional, not allelic
Overall
CADD	20.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DOT1L
Protein: p.Asp744Glu
Coding: c.2232C>G
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2216589 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB

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

Similar variants

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
DOT1L p.Thr957Ile 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-asp744glu (accessed [today's date]).

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