# NM_170606.3(KMT2C):c.4986del (p.Asn1663fs)

https://sugi.bio/variant/kmt2c-p-asn1663fs

## Summary

**KMT2C p.Asn1663fs (c.4986del)** is classified **Likely pathogenic** in KMT2C (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-05).

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the KMT2C gene that is considered likely disease-causing, submitted by 1 submitter.

*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 | [KMT2C](https://sugi.bio/atlas/gene/KMT2C/) |
| Protein change (HGVS p.) | p.Asn1663fs |
| Coding change (HGVS c.) | c.4986del |
| MANE Select transcript | [NM_170606](https://www.ncbi.nlm.nih.gov/nuccore/NM_170606) |
| Variant type | Deletion |
| Location | chr7:152187284-152187284 (GRCh38) |
| ClinVar | [VCV4856819](https://www.ncbi.nlm.nih.gov/clinvar/variation/4856819/) |

**All HGVS expressions:** `NC_000007.13:g.151884372del`, `NC_000007.14:g.152187287del`, `NG_033948.1:g.253722del`, `NM_170606.3:c.4986del`

## 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 1.21, GERP 3.11, phastCons 0.131 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.202, 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 33 of 59**, 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.

*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}

**KMT2C** population constraint: LOEUF 0.202, pLI 1, missense-Z 4.3119; 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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (in klefs2).

**9 experimental structure(s)** (PDB): [2YSM](https://www.rcsb.org/structure/2YSM), [2YUK](https://www.rcsb.org/structure/2YUK), [3UVL](https://www.rcsb.org/structure/3UVL), [4ERY](https://www.rcsb.org/structure/4ERY), [5F59](https://www.rcsb.org/structure/5F59), [5F6K](https://www.rcsb.org/structure/5F6K).

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

*Describes the biological roles of KMT2C (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:** KMT2C's established molecular role includes RNA binding.


### Pathways affected {#pathways}

KMT2C participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | 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:** RNA binding, histone methyltransferase activity, histone H3K4 methyltransferase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-05.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dasa | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-04-05 |

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

## Similar variants {#similar}

Related KMT2C variant pages (same residue, condition, or type): [KMT2C c.1185-20_1185-7del](/variant/kmt2c-c-1185-minus-20-1185-minus-7del), [KMT2C p.Arg490fs](/variant/kmt2c-p-arg490fs), [KMT2C p.Asn2848fs](/variant/kmt2c-p-asn2848fs), [KMT2C p.His2950fs](/variant/kmt2c-p-his2950fs), [KMT2C p.Leu1155_Val1156insTer](/variant/kmt2c-p-leu1155-val1156inster), [KMT2C p.Thr610fs](/variant/kmt2c-p-thr610fs), [KMT2C c.162-7del](/variant/kmt2c-c-162-minus-7del), [KMT2C c.1622-6del](/variant/kmt2c-c-1622-minus-6del).

### 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 4856819). 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.*