# NM_014159.7(SETD2):c.1748_1751del (p.Lys583fs)

https://sugi.bio/variant/setd2-p-lys583fs

## Summary

**SETD2 p.Lys583fs (c.1748_1751del)** is classified **Pathogenic** in SETD2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2021-05-13). No gnomAD frequency available for this variant; Associated with Luscan-Lumish syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2043159037 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SETD2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Luscan-Lumish 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013789/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SETD2](https://sugi.bio/atlas/gene/SETD2/) |
| Protein change (HGVS p.) | p.Lys583fs |
| Coding change (HGVS c.) | c.1748_1751del |
| MANE Select transcript | [NM_014159](https://www.ncbi.nlm.nih.gov/nuccore/NM_014159) |
| dbSNP | [rs2043159037](https://www.ncbi.nlm.nih.gov/snp/rs2043159037/) |
| Variant type | Deletion |
| Location | chr3:47122885-47122888 (GRCh38) |
| ClinVar | [VCV1164031](https://www.ncbi.nlm.nih.gov/clinvar/variation/1164031/) |

**All HGVS expressions:** `LRG_775:g.46090_46093del`, `NC_000003.11:g.47164377_47164380del`, `NC_000003.12:g.47122887_47122890del`, `NG_032091.1:g.46090_46093del`, `NM_001349370.3:c.1616_1619del`, `NM_014159.7:c.1748_1751del`, `NM_014159.7:c.1748_1751delAACA`, `NR_146158.3:n.1937_1940del`

## 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 -0.669, GERP -1.31, phastCons 0.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.176, 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 3 of 21**, 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SETD2** population constraint: LOEUF 0.176, pLI 1, missense-Z 4.1571; 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):

- **SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome** — Strong (AD)
- **SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth** — Definitive (AD)

## Protein context {#protein}

Residue **583** lies in a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation).

AlphaFold model confidence (whole protein): pLDDT 43.81, 12% of residues very-high.

**43 experimental structure(s)** (PDB): [2A7O](https://www.rcsb.org/structure/2A7O), [2MDC](https://www.rcsb.org/structure/2MDC), [2MDI](https://www.rcsb.org/structure/2MDI), [2MDJ](https://www.rcsb.org/structure/2MDJ), [4FMU](https://www.rcsb.org/structure/4FMU), [4H12](https://www.rcsb.org/structure/4H12) — incl. mutant structure 2MDI.

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

*Describes the biological roles of SETD2 (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:** SETD2's established molecular role includes protein-lysine N-methyltransferase activity.


### Pathways affected {#pathways}

SETD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |

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

**Molecular function:** protein-lysine N-methyltransferase activity, alpha-tubulin binding, histone H3K36 methyltransferase activity.

**Biological process:** mismatch repair, transcription elongation by RNA polymerase II, positive regulation of autophagy, regulation of double-strand break repair via homologous recombination, regulation of mRNA export from nucleus, peptidyl-lysine trimethylation.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-05-13.

**Submitter consensus:** unanimous (1/1 Pathogenic).

**Submission history:** 2 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Pediatric Genetics Clinic, Sheba Medical Center | Pathogenic | no assertion criteria provided | clinical testing | 2021-05-13 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital |  | criteria provided, single submitter | clinical testing | 2025-03-04 |

## Associated conditions {#conditions}

[Luscan-Lumish syndrome](https://sugi.bio/atlas/disease/luscan-lumish-syndrome/).

**Reported phenotype names (ClinVar):** Luscan-Lumish syndrome, Neoplasm.

## Similar variants {#similar}

Related SETD2 variant pages (same residue, condition, or type): [SETD2 c.5015+39_5015+40del](/variant/setd2-c-5015-plus-39-5015-plus-40del), [SETD2 c.6110-27_6110-26del](/variant/setd2-c-6110-minus-27-6110-minus-26del), [SETD2 p.Gly1726fs](/variant/setd2-p-gly1726fs), [SETD2 p.Lys1486fs](/variant/setd2-p-lys1486fs), [SETD2 p.Ser2238fs](/variant/setd2-p-ser2238fs), [SETD2 p.Gln2334_Ile2336del](/variant/setd2-p-gln2334-ile2336del), [SETD2 p.Ser1268del](/variant/setd2-p-ser1268del), [SETD2 p.Ser2271del](/variant/setd2-p-ser2271del).

### 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 1164031). 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.*