Is DOT1L p.Phe547Leu (c.1641T>G) pathogenic?

DOT1L p.Phe547Leu (c.1641T>G) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely pathogenic (0.9911); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DOT1L p.Phe547Leu (c.1641T>G)?

DOT1L p.Phe547Leu (c.1641T>G) is associated with Inborn genetic diseases (ClinVar).

How common is DOT1L p.Phe547Leu (c.1641T>G) in the general population?

DOT1L p.Phe547Leu (c.1641T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOT1L p.Phe547Leu (c.1641T>G)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

DOT1L p.Phe547Leu

c.1641T>G · rs772701533 · VCV3085391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic · top 9% in DOT1L
REVEL	0.237	benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -2.4, phastCons 0.97
Regional constraint	o/e 0.66	unconstrained · MANE · 5,186 bp · p 2.1e-07 · regional, not allelic
Overall
CADD	17.21	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

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.Phe547Leu
Coding: c.1641T>G
MANE Select: NM_032482
dbSNP: rs772701533
Type: single nucleotide variant
Location: chr19:2213622 (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

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-phe547leu (accessed [today's date]).

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