# NM_003482.4(KMT2D):c.2173_2174del (p.Leu725fs)

https://sugi.bio/variant/kmt2d-p-leu725fs

## Summary

**KMT2D p.Leu725fs (c.2173_2174del)** is classified **Pathogenic/Likely pathogenic** in KMT2D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-27). No gnomAD frequency available for this variant; Associated with KMT2D-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2120671121 · 3 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the KMT2D gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to KMT2D-related disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KMT2D](https://sugi.bio/atlas/gene/KMT2D/) |
| Protein change (HGVS p.) | p.Leu725fs |
| Coding change (HGVS c.) | c.2173_2174del |
| MANE Select transcript | [NM_003482](https://www.ncbi.nlm.nih.gov/nuccore/NM_003482) |
| dbSNP | [rs2120671121](https://www.ncbi.nlm.nih.gov/snp/rs2120671121/) |
| Variant type | Deletion |
| Location | chr12:49051509-49051510 (GRCh38) |
| ClinVar | [VCV1069469](https://www.ncbi.nlm.nih.gov/clinvar/variation/1069469/) |

**All HGVS expressions:** `NC_000012.11:g.49445292_49445293del`, `NC_000012.12:g.49051509_49051510del`, `NG_027827.1:g.8815_8816del`, `NM_003482.4:c.2173_2174del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -1.217, GERP 0.177 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.141, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 55**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**KMT2D** population constraint: LOEUF 0.141, pLI 1, missense-Z 4.7249; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Kabuki syndrome 1** — Definitive (AD)

## Protein context {#protein}

Residue **725** lies in a UniProt-annotated variant site (in kabuk1); the 'disordered' region.

**11 experimental structure(s)** (PDB): [3UVK](https://www.rcsb.org/structure/3UVK), [4ERQ](https://www.rcsb.org/structure/4ERQ), [4Z4P](https://www.rcsb.org/structure/4Z4P), [6O7G](https://www.rcsb.org/structure/6O7G), [8U2Y](https://www.rcsb.org/structure/8U2Y), [9ATN](https://www.rcsb.org/structure/9ATN).

## What this gene does {#gene-function}

*Describes the biological roles of KMT2D (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** KMT2D's established molecular role includes transcription cis-regulatory region binding. p.Leu725fs falls in the disordered region. In Reactome, KMT2D is annotated in disease pathway(s) including **Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome**.

**Disease mechanism (Reactome):** KMT2D loss or alteration is curated in [Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome](https://reactome.org/content/detail/R-HSA-9944997).

### Pathways affected {#pathways}

KMT2D participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome](https://reactome.org/content/detail/R-HSA-9944997) | curated |
| [Epigenetic regulation of gene expression by MLL3 and MLL4 complexes](https://reactome.org/content/detail/R-HSA-9818564) | curated |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding.

**Biological process:** positive regulation of cell population proliferation, positive regulation of intracellular estrogen receptor signaling pathway, response to estrogen, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-27.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-08 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-11-27 |

## Associated conditions {#conditions}

[KMT2D-related disorder](https://sugi.bio/atlas/disease/kmt2d-related-disorder/), [Kabuki syndrome 1](https://sugi.bio/atlas/disease/kabuki-syndrome-1/), [Kabuki syndrome](https://sugi.bio/atlas/disease/kabuki-syndrome/).

**Reported phenotype names (ClinVar):** KMT2D-related disorder, Kabuki syndrome, Kabuki syndrome 1, KMT2D-Related Disorders, NIIKAWA-KUROKI SYNDROME, Kabuki make-up syndrome, KMT2D-Related Kabuki Syndrome.

## Similar variants {#similar}

Related KMT2D variant pages (same residue, condition, or type): [KMT2D p.Leu725Gln](/variant/kmt2d-p-leu725gln), [KMT2D p.Leu725_Leu726insGluGluSerProLeu](/variant/kmt2d-p-leu725-leu726insglugluserproleu), [KMT2D c.3907-2_3907-1del](/variant/kmt2d-c-3907-minus-2-3907-minus-1del), [KMT2D p.Ala3808fs](/variant/kmt2d-p-ala3808fs), [KMT2D p.Arg2460fs](/variant/kmt2d-p-arg2460fs), [KMT2D p.Arg4666fs](/variant/kmt2d-p-arg4666fs), [KMT2D p.Arg845fs](/variant/kmt2d-p-arg845fs), [KMT2D p.Asn5480fs](/variant/kmt2d-p-asn5480fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1069469). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*