# NM_014727.3(KMT2B):c.6976A>G (p.Met2326Val)

https://sugi.bio/variant/kmt2b-p-met2326val

## Summary

**KMT2B p.Met2326Val (c.6976A>G)** is classified **Uncertain significance** in KMT2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2645); Very rare (popmax 0.00135%, afr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1039247530 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.00135%, afr)

## For patients & families {#patients}

This is a change in the KMT2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [KMT2B](https://sugi.bio/atlas/gene/KMT2B/) |
| Protein change (HGVS p.) | p.Met2326Val |
| Coding change (HGVS c.) | c.6976A>G |
| MANE Select transcript | [NM_014727](https://www.ncbi.nlm.nih.gov/nuccore/NM_014727) |
| dbSNP | [rs1039247530](https://www.ncbi.nlm.nih.gov/snp/rs1039247530/) |
| Variant type | single nucleotide variant |
| Location | chr19:35733613-35733613 (GRCh38) |
| ClinVar | [VCV2579594](https://www.ncbi.nlm.nih.gov/clinvar/variation/2579594/) |

**All HGVS expressions:** `NC_000019.10:g.35733613A>G`, `NC_000019.9:g.36224514A>G`, `NG_052906.1:g.20595A>G`, `NM_014727.3:c.6976A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2645)
- REVEL 0.472 (indeterminate)
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.156, GERP 1.78, 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 22.3**. 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 1.09** across the covering region of the MANE Select transcript (35,730,849–35,736,752), spanning 5,903 bp. Chi-square p 0.013. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.33** (loss), gain 0.01 / loss 0.33. 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 **0.00135%** (afr) · FAF95 8e-05% · FAF99 5.4e-05% · 1/74,246 in the highest group · 5/1,585,746 alleles overall — very rare (popmax 0.00135%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00135% | 74,246 |
| European (non-Finnish) | 0.000343% | 291,588 |

*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}

**KMT2B** population constraint: LOEUF 0.127, pLI 1, missense-Z 2.7377; 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):

- **complex neurodevelopmental disorder with motor features** — Definitive (AD)

## Protein context {#protein}

Residue **2326** lies in a UniProt-annotated variant site (in dyt28); a UniProt-annotated variant site (in mrd68); the 'disordered' region.

**4 experimental structure(s)** (PDB): [3UVM](https://www.rcsb.org/structure/3UVM), [4ERZ](https://www.rcsb.org/structure/4ERZ), [4PZI](https://www.rcsb.org/structure/4PZI), [7BRE](https://www.rcsb.org/structure/7BRE).

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

*Describes the biological roles of KMT2B (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:** KMT2B's established molecular role includes zinc ion binding. p.Met2326Val falls in the disordered region.


### Pathways affected {#pathways}

KMT2B participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | 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 |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | electronic |

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

**Molecular function:** zinc ion binding, histone H3K4 methyltransferase activity, unmethylated CpG binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-08 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related KMT2B variant pages (same residue, condition, or type): [KMT2B p.Met2326Arg](/variant/kmt2b-p-met2326arg), [KMT2B p.Ala1616Val](/variant/kmt2b-p-ala1616val), [KMT2B p.Ala2641Thr](/variant/kmt2b-p-ala2641thr), [KMT2B p.Arg142Ter](/variant/kmt2b-p-arg142ter), [KMT2B p.Arg1597Trp](/variant/kmt2b-p-arg1597trp), [KMT2B p.Arg1705Ter](/variant/kmt2b-p-arg1705ter), [KMT2B p.Arg2565Gly](/variant/kmt2b-p-arg2565gly), [KMT2B p.Arg2610Cys](/variant/kmt2b-p-arg2610cys).

### 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 2579594). 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.*