Is KMT2D p.Leu289Ser (c.866T>C) pathogenic?

KMT2D p.Leu289Ser (c.866T>C) is classified Uncertain significance in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Leu289Ser (c.866T>C)?

KMT2D p.Leu289Ser (c.866T>C) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Leu289Ser (c.866T>C) in the general population?

KMT2D p.Leu289Ser (c.866T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KMT2D p.Leu289Ser (c.866T>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

KMT2D p.Leu289Ser

c.866T>C · VCV4775098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Kabuki syndrome

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 3% in KMT2D
REVEL	0.59	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,303 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: KMT2D
Protein: p.Leu289Ser
Coding: c.866T>C
MANE Select: NM_003482
Type: single nucleotide variant
Location: chr12:49053295 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 289: a UniProt-annotated variant site (in kabuk1); a β-strand

Full KMT2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Kabuki syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KMT2D p.Leu289Ter Pathogenic ★ same residue
KMT2D p.Leu289= Likely benign ★ same residue
KMT2D c.10740+1G>A Pathogenic ★★ same condition
KMT2D c.14075+1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.16338+2T>C Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.4132-2A>G Pathogenic ★★ same condition
KMT2D c.5189-2A>G Pathogenic/Likely pathogenic ★★ same condition
KMT2D p.Arg1615Ter 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/kmt2d-p-leu289ser (accessed [today's date]).

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