Is KMT2D p.Leu725Gln (c.2174T>A) pathogenic?

KMT2D p.Leu725Gln (c.2174T>A) is classified Benign/Likely benign in KMT2D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-09). AlphaMissense: likely benign (0.0952); Very rare (popmax 0.000593%, nfe); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Leu725Gln (c.2174T>A)?

KMT2D p.Leu725Gln (c.2174T>A) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Leu725Gln (c.2174T>A) in the general population?

KMT2D p.Leu725Gln (c.2174T>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about KMT2D p.Leu725Gln (c.2174T>A)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

KMT2D p.Leu725Gln

c.2174T>A · rs757459288 · VCV2966018

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Kabuki syndrome

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.206	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.28, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 2,394 bp · p 0.74 · regional, not allelic
Overall
CADD	17.34	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

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,732 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,676 alleles · very rare exomes 7/1,461,478 · genomes 0/152,198 · joint denominator

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: KMT2D
Protein: p.Leu725Gln
Coding: c.2174T>A
MANE Select: NM_003482
dbSNP: rs757459288
Type: single nucleotide variant
Location: chr12:49051509 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 725: a UniProt-annotated variant site (in kabuk1); the 'disordered' region

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.Leu725fs Pathogenic/Likely pathogenic ★★ same residue
KMT2D p.Leu725_Leu726insGluGluSerProLeu Uncertain significance ★ 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-leu725gln (accessed [today's date]).

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