Is DOT1L p.Gln654Arg (c.1961A>G) pathogenic?

DOT1L p.Gln654Arg (c.1961A>G) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-23). AlphaMissense: likely benign (0.1525); Very rare (popmax 8.57e-05%, nfe).

How common is DOT1L p.Gln654Arg (c.1961A>G) in the general population?

DOT1L p.Gln654Arg (c.1961A>G) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about DOT1L p.Gln654Arg (c.1961A>G)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

DOT1L p.Gln654Arg

c.1961A>G · VCV4689750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -6.05	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 8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,186 bp · p 2.1e-07 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 8.57e-05% European (non-Finnish) · 1/1,166,310 alleles

Overall 6.93e-05% 1/1,442,184 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.Gln654Arg
Coding: c.1961A>G
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2216318 (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-gln654arg (accessed [today's date]).

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