# NM_003482.4(KMT2D):c.3710C>T (p.Ser1237Phe)

https://sugi.bio/variant/kmt2d-p-ser1237phe

## Summary

**KMT2D p.Ser1237Phe (c.3710C>T)** is classified **Conflicting classifications of pathogenicity** in KMT2D (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.6882); Very rare (popmax 0.00267%, afr); Associated with Kabuki syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs374437749 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the KMT2D gene that is of uncertain or conflicting significance (submitters disagree on it), 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.Ser1237Phe |
| Coding change (HGVS c.) | c.3710C>T |
| MANE Select transcript | [NM_003482](https://www.ncbi.nlm.nih.gov/nuccore/NM_003482) |
| dbSNP | [rs374437749](https://www.ncbi.nlm.nih.gov/snp/rs374437749/) |
| Variant type | single nucleotide variant |
| Location | chr12:49049878-49049878 (GRCh38) |
| ClinVar | [VCV2635863](https://www.ncbi.nlm.nih.gov/clinvar/variation/2635863/) |

**All HGVS expressions:** `NC_000012.11:g.49443661G>A`, `NC_000012.12:g.49049878G>A`, `NG_027827.1:g.10447C>T`, `NG_086019.1:g.1018G>A`, `NM_003482.4:c.3710C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6882)
- REVEL 0.368 (indeterminate)
- Conservation: phyloP 11.837, GERP 2.19, phastCons 1 — highly conserved (agrees)
- **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 24.1**. 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 0.89** across the covering region of the MANE Select transcript (49,048,717–49,050,661), spanning 1,944 bp. Chi-square p 0.018. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for KMT2D (2,340 scored positions, the nearest 9 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.0013% · FAF99 0.00108% · 2/74,936 in the highest group · 29/1,613,774 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,821 |
| African / African-American (grpmax) | 0.00267% | 37,468 |
| European (non-Finnish) | 0.00195% | 51,299 |
| South Asian | 0.0011% | 91,086 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **1237** 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.Ser1237Phe 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-20.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign).

**Submission history:** 2 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-10-20 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related KMT2D variant pages (same residue, condition, or type): [KMT2D p.Ser1237=](/variant/kmt2d-p-ser1237), [KMT2D p.Ser1237Ala](/variant/kmt2d-p-ser1237ala), [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 2026-10-15); 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 2635863). 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.*