# NM_014159.7(SETD2):c.1687A>G (p.Ile563Val)

https://sugi.bio/variant/setd2-p-ile563val

## Summary

**SETD2 p.Ile563Val (c.1687A>G)** is classified **Benign/Likely benign** in SETD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-06). AlphaMissense: likely benign (0.0591); Very rare (popmax 0.00835%, amr); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs587778668 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00835%, amr)

## For patients & families {#patients}

This is a change in the SETD2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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 | [SETD2](https://sugi.bio/atlas/gene/SETD2/) |
| Protein change (HGVS p.) | p.Ile563Val |
| Coding change (HGVS c.) | c.1687A>G |
| MANE Select transcript | [NM_014159](https://www.ncbi.nlm.nih.gov/nuccore/NM_014159) |
| dbSNP | [rs587778668](https://www.ncbi.nlm.nih.gov/snp/rs587778668/) |
| Variant type | single nucleotide variant |
| Location | chr3:47122949-47122949 (GRCh38) |
| ClinVar | [VCV135210](https://www.ncbi.nlm.nih.gov/clinvar/variation/135210/) |

**All HGVS expressions:** `LRG_775:g.46029A>G`, `LRG_775t1:c.1687A>G`, `NC_000003.11:g.47164439T>C`, `NC_000003.12:g.47122949T>C`, `NG_032091.1:g.46029A>G`, `NM_001349370.3:c.1555A>G`, `NM_014159.7:c.1687A>G`, `NR_146158.3:n.1876A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0591)
- REVEL 0.088 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.475 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.931, GERP -4.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.148**. 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 1.03** across the covering region of the MANE Select transcript (47,120,292–47,123,521), spanning 3,229 bp. Chi-square p 0.25. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00835%** (amr) · FAF95 0.00324% · FAF99 0.00207% · 5/59,846 in the highest group · 8/1,613,326 alleles overall — very rare (popmax 0.00835%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00835% | 11,969 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,032 |
| African / African-American | 0.00134% | 74,880 |
| European (non-Finnish) | 8.48e-05% | 1,179,647 |

*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 **563** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-06.

**Submitter consensus:** conflicting (2 Benign, 1 not provided, 1 Likely benign).

**Submission history:** 4 submissions (2013–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2021-12-03 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Luscan-Lumish syndrome](https://sugi.bio/atlas/disease/luscan-lumish-syndrome/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, Luscan-Lumish syndrome, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related SETD2 variant pages (same residue, condition, or type): [SETD2 p.Ile563Thr](/variant/setd2-p-ile563thr), [SETD2 p.Arg1598Ter](/variant/setd2-p-arg1598ter), [SETD2 p.Arg1740Gln](/variant/setd2-p-arg1740gln), [SETD2 p.Arg1740Trp](/variant/setd2-p-arg1740trp), [SETD2 c.4715+5G>A](/variant/setd2-c-4715-plus-5g-a), [SETD2 p.Ala1121Thr](/variant/setd2-p-ala1121thr), [SETD2 p.Ala679Val](/variant/setd2-p-ala679val), [SETD2 p.Arg1065Cys](/variant/setd2-p-arg1065cys).

### 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 135210). 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.*