Is DOT1L p.Pro391Thr (c.1171C>A) pathogenic?

DOT1L p.Pro391Thr (c.1171C>A) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-08). AlphaMissense: likely benign (0.1536); Absent from gnomAD v4.1; Associated with Nil-Deshwar neurodevelopmental syndrome.

What condition is associated with DOT1L p.Pro391Thr (c.1171C>A)?

DOT1L p.Pro391Thr (c.1171C>A) is associated with Nil-Deshwar neurodevelopmental syndrome (ClinVar).

How common is DOT1L p.Pro391Thr (c.1171C>A) in the general population?

DOT1L p.Pro391Thr (c.1171C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOT1L p.Pro391Thr (c.1171C>A)?

AlphaMissense predicts likely benign (score 0.1536) — an in-silico prediction, not a clinical call.

DOT1L p.Pro391Thr

c.1171C>A · VCV4883678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1536 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nil-Deshwar neurodevelopmental syndrome

Computational evidence

Protein change
AlphaMissense	0.1536	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -6.78	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 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 758 bp · p 0.9 · regional, not allelic
Overall
CADD	24.6	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.Pro391Thr
Coding: c.1171C>A
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2210675 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB
Residue 391: 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

Nil-Deshwar neurodevelopmental syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOT1L p.Glu134Lys Uncertain significance ★ ⚠ same condition
DOT1L p.His109Arg Uncertain significance ★ ⚠ same condition
DOT1L p.Ala1041Ser Likely benign ★ same condition
DOT1L p.Arg853Cys Pathogenic ⚠ same condition
DOT1L p.Asp157Asn Pathogenic same condition
DOT1L p.Cys45Gly Pathogenic ⚠ same condition
DOT1L p.Glu123Lys Pathogenic same condition
DOT1L p.Glu129Lys Pathogenic 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-pro391thr (accessed [today's date]).

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