# NM_003482.4(KMT2D):c.2174T>A (p.Leu725Gln)

https://sugi.bio/variant/kmt2d-p-leu725gln

## Summary

**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.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs757459288 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the KMT2D gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Kabuki syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006810/index) · [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.Leu725Gln |
| Coding change (HGVS c.) | c.2174T>A |
| MANE Select transcript | [NM_003482](https://www.ncbi.nlm.nih.gov/nuccore/NM_003482) |
| dbSNP | [rs757459288](https://www.ncbi.nlm.nih.gov/snp/rs757459288/) |
| Variant type | single nucleotide variant |
| Location | chr12:49051509-49051509 (GRCh38) |
| ClinVar | [VCV2966018](https://www.ncbi.nlm.nih.gov/clinvar/variation/2966018/) |

**All HGVS expressions:** `NC_000012.11:g.49445292A>T`, `NC_000012.12:g.49051509A>T`, `NG_027827.1:g.8816T>A`, `NM_003482.4:c.2174T>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0952)
- REVEL 0.206 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 2.058, GERP 0.275, phastCons 0.001 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 17.34**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (49,050,662–49,053,056), spanning 2,394 bp. Chi-square p 0.74. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,732 in the highest group · 7/1,613,676 alleles overall — very rare (popmax 0.000593%, nfe).

*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.Leu725Gln 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-09.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2023-06-15 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-09 |

## Associated conditions {#conditions}

[Kabuki syndrome](https://sugi.bio/atlas/disease/kabuki-syndrome/).

**Reported phenotype names (ClinVar):** Kabuki syndrome, not specified, AllHighlyPenetrant, NIIKAWA-KUROKI SYNDROME, Kabuki make-up syndrome.

## Same-residue context {#hotspot}

Residue **725** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [KMT2D p.Leu725fs](/variant/kmt2d-p-leu725fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KMT2D variant pages (same residue, condition, or type): [KMT2D p.Leu725fs](/variant/kmt2d-p-leu725fs), [KMT2D p.Leu725_Leu726insGluGluSerProLeu](/variant/kmt2d-p-leu725-leu726insglugluserproleu), [KMT2D c.10740+1G>A](/variant/kmt2d-c-10740-plus-1g-a), [KMT2D c.14075+1G>A](/variant/kmt2d-c-14075-plus-1g-a), [KMT2D c.16338+2T>C](/variant/kmt2d-c-16338-plus-2t-c), [KMT2D c.4132-2A>G](/variant/kmt2d-c-4132-minus-2a-g), [KMT2D c.5189-2A>G](/variant/kmt2d-c-5189-minus-2a-g), [KMT2D p.Arg1615Ter](/variant/kmt2d-p-arg1615ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2966018). 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.*