# NM_003482.4(KMT2D):c.5477G>T (p.Gly1826Val)

https://sugi.bio/variant/kmt2d-p-gly1826val

## Summary

**KMT2D p.Gly1826Val (c.5477G>T)** is classified **Benign** in KMT2D (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.076); Rare (popmax 0.745%, sas); Associated with Kabuki syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs574989512 · 6 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.745%, sas)

## For patients & families {#patients}

This is a change in the KMT2D gene that is classified as benign — not considered disease-causing, submitted by 6 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.Gly1826Val |
| Coding change (HGVS c.) | c.5477G>T |
| MANE Select transcript | [NM_003482](https://www.ncbi.nlm.nih.gov/nuccore/NM_003482) |
| dbSNP | [rs574989512](https://www.ncbi.nlm.nih.gov/snp/rs574989512/) |
| Variant type | single nucleotide variant |
| Location | chr12:49043419-49043419 (GRCh38) |
| ClinVar | [VCV134679](https://www.ncbi.nlm.nih.gov/clinvar/variation/134679/) |

**All HGVS expressions:** `NC_000012.11:g.49437202C>A`, `NC_000012.12:g.49043419C>A`, `NG_027827.1:g.16906G>T`, `NM_003482.4:c.5477G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.076)
- REVEL 0.379 (indeterminate)
- SpliceAI predicts **acceptor gain** (Δ 0.60) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.914, GERP 1.07, phastCons 1 — 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 24.6**. 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 0.79** across the covering region of the MANE Select transcript (49,041,494–49,046,610), spanning 5,116 bp. Chi-square p 1e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.08**, donor loss **0.00**, acceptor gain **0.60**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.60**, donor gain **0.00**.
- Pangolin: Δ**0.25** (gain), gain 0.25 / loss 0.07. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.745%** (sas) · FAF95 0.699% · FAF99 0.68% · 679/91,082 in the highest group · 707/1,613,920 alleles overall — rare (popmax 0.745%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.745% | 134 |
| Remaining individuals (not grpmax-eligible) | 0.0336% | 2,975 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.00533% | 18,756 |
| European (non-Finnish) | 0.00017% | 589,918 |

*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 **1826** 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.Gly1826Val 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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-06.

**Submitter consensus:** conflicting (5 Benign, 1 not provided).

**Submission history:** 6 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-06 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-10-29 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-12-13 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Kabuki syndrome, not specified, not provided, NIIKAWA-KUROKI SYNDROME, Kabuki make-up syndrome, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related KMT2D variant pages (same residue, condition, or type): [KMT2D p.Gly1826Ala](/variant/kmt2d-p-gly1826ala), [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), [KMT2D p.Arg1903Ter](/variant/kmt2d-p-arg1903ter).

### 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 134679). 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.*