Is DOT1L p.Pro1029Ser (c.3085C>T) pathogenic?

DOT1L p.Pro1029Ser (c.3085C>T) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00133%, afr).

How common is DOT1L p.Pro1029Ser (c.3085C>T) in the general population?

DOT1L p.Pro1029Ser (c.3085C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DOT1L p.Pro1029Ser (c.3085C>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

DOT1L p.Pro1029Ser

c.3085C>T · VCV3600887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -3.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.5	GERP 0.003, phastCons 0.001
Regional constraint	o/e 1.13	unconstrained · MANE · 7,763 bp · p 0.00016 · regional, not allelic
Overall
CADD	15.93	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 0.00133% African / African-American · 1/75,054 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000479% 7/1,460,820 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,054
South Asian	0.0011%	91,084
European (non-Finnish)	0.000424%	235,988

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.Pro1029Ser
Coding: c.3085C>T
MANE Select: NM_032482
Type: single nucleotide variant
Location: chr19:2222254 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB
Residue 1029: the 'disordered' region

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-pro1029ser (accessed [today's date]).

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