# NM_014159.7(SETD2):c.5127T>G (p.Ser1709=)

https://sugi.bio/variant/setd2-p-ser1709

## Summary

**SETD2 p.Ser1709= (c.5127T>G)** is classified **Benign** in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-06). Rare (popmax 0.223%, eas); Associated with Luscan-Lumish syndrome.

**At a glance:** Benign · review: Single submitter · rsID rs776440125 · 1 submitter · 1 linked condition · rare (popmax 0.223%, eas)

## For patients & families {#patients}

This is a change in the SETD2 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, 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.Ser1709= |
| Coding change (HGVS c.) | c.5127T>G |
| MANE Select transcript | [NM_014159](https://www.ncbi.nlm.nih.gov/nuccore/NM_014159) |
| dbSNP | [rs776440125](https://www.ncbi.nlm.nih.gov/snp/rs776440125/) |
| Variant type | single nucleotide variant |
| Location | chr3:47097970-47097970 (GRCh38) |
| ClinVar | [VCV745433](https://www.ncbi.nlm.nih.gov/clinvar/variation/745433/) |

**All HGVS expressions:** `LRG_775:g.71008T>G`, `LRG_775t1:c.5127T>G`, `NC_000003.11:g.47139460A>C`, `NC_000003.12:g.47097970A>C`, `NG_032091.1:g.71008T>G`, `NM_001349370.3:c.4995T>G`, `NM_014159.7:c.5127T>G`, `NR_146158.3:n.5316T>G`

## 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 2.588, GERP -4.65, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.346**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.23 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.223%** (eas) · FAF95 0.187% · FAF99 0.174% · 100/44,874 in the highest group · 101/1,613,866 alleles overall — rare (popmax 0.223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.223% | 449 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |

*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 **1709** lies in a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with tuba1a' region.

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. p.Ser1709= falls in the interaction with tuba1a region.


### 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}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-08-06 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related SETD2 variant pages (same residue, condition, or type): [SETD2 p.Arg1598Ter](/variant/setd2-p-arg1598ter), [SETD2 p.Arg1740Gln](/variant/setd2-p-arg1740gln), [SETD2 p.Arg1740Trp](/variant/setd2-p-arg1740trp), [SETD2 p.Ala1121Thr](/variant/setd2-p-ala1121thr), [SETD2 p.Ala679Val](/variant/setd2-p-ala679val), [SETD2 p.Arg1065Cys](/variant/setd2-p-arg1065cys), [SETD2 p.Arg329Gln](/variant/setd2-p-arg329gln), [SETD2 p.Arg368Gln](/variant/setd2-p-arg368gln).

### 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 745433). 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.*