Is DOT1L p.Ala1230Val (c.3689C>T) pathogenic?

DOT1L p.Ala1230Val (c.3689C>T) is classified Uncertain significance in DOT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0194%, afr); Associated with Inborn genetic diseases.

What condition is associated with DOT1L p.Ala1230Val (c.3689C>T)?

DOT1L p.Ala1230Val (c.3689C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DOT1L p.Ala1230Val (c.3689C>T) in the general population?

DOT1L p.Ala1230Val (c.3689C>T) is ultra-rare (popmax 0.0194%, afr) (gnomAD).

What do computational predictors say about DOT1L p.Ala1230Val (c.3689C>T)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

DOT1L p.Ala1230Val

c.3689C>T · rs781060698 · VCV2270782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.09	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 -0.35	GERP -1.4
Regional constraint	o/e 1.13	unconstrained · MANE · 7,763 bp · p 0.00016 · regional, not allelic
Overall
CADD	8.337	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 0.0194% African / African-American · 14/72,132 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00937%

Overall 0.00223% 34/1,522,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0194%	5,152
Middle Eastern	0.0174%	5,736
Admixed American	0.00407%	24,540
South Asian	0.00389%	25,699
Remaining individualsnot grpmax-eligible	0.00342%	29,268
European (non-Finnish)	0.00106%	94,467

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.Ala1230Val
Coding: c.3689C>T
MANE Select: NM_032482
dbSNP: rs781060698
Type: single nucleotide variant
Location: chr19:2226210 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.11 · 48 PDB
Residue 1230: the 'disordered' region

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.Ala1230Thr Likely benign ★ same residue
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.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-ala1230val (accessed [today's date]).

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