# NM_015559.3(SETBP1):c.1082_1083dup (p.Phe362fs)

https://sugi.bio/variant/setbp1-p-phe362fs

## Summary

**SETBP1 p.Phe362fs (c.1082_1083dup)** is classified **Pathogenic** in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-21). No gnomAD frequency available for this variant; Associated with intellectual disability, autosomal dominant 29.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2071314703 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SETBP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual disability, autosomal dominant 29.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | SETBP1 is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013379/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SETBP1](https://sugi.bio/atlas/gene/SETBP1/) |
| Protein change (HGVS p.) | p.Phe362fs |
| Coding change (HGVS c.) | c.1082_1083dup |
| MANE Select transcript | [NM_015559](https://www.ncbi.nlm.nih.gov/nuccore/NM_015559) |
| dbSNP | [rs2071314703](https://www.ncbi.nlm.nih.gov/snp/rs2071314703/) |
| Variant type | Duplication |
| Location | chr18:44950421-44950422 (GRCh38) |
| ClinVar | [VCV976037](https://www.ncbi.nlm.nih.gov/clinvar/variation/976037/) |

**All HGVS expressions:** `LRG_1150:g.275250_275251dup`, `LRG_1150t1:c.1082_1083dup`, `NC_000018.10:g.44950422_44950423dup`, `NC_000018.9:g.42530387_42530388dup`, `NG_027527.2:g.275250_275251dup`, `NM_001379141.1:c.1082_1083dup`, `NM_001379142.1:c.1082_1083dup`, `NM_015559.3:c.1082_1083dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.641, GERP 1.78, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.143, 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 4 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**SETBP1** population constraint: LOEUF 0.143, pLI 1, missense-Z 1.8562; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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** — Definitive (AD)
- **Schinzel-Giedion syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **362** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 43.30, 1% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-03-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2019-03-21 |

## Associated conditions {#conditions}

[intellectual disability, autosomal dominant 29](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-29/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 29, SETBP1 Haploinsufficiency Disorder, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 29.

## Similar variants {#similar}

Related SETBP1 variant pages (same residue, condition, or type): [SETBP1 p.Glu16fs](/variant/setbp1-p-glu16fs), [SETBP1 p.Ala1245fs](/variant/setbp1-p-ala1245fs), [SETBP1 p.Glu697fs](/variant/setbp1-p-glu697fs), [SETBP1 p.Pro563fs](/variant/setbp1-p-pro563fs), [SETBP1 c.(540+1_541-1](/variant/setbp1-c-540-plus-1-541-minus-1), [SETBP1 p.Arg530Ter](/variant/setbp1-p-arg530ter), [SETBP1 p.Arg544Ter](/variant/setbp1-p-arg544ter), [SETBP1 p.Arg589Ter](/variant/setbp1-p-arg589ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 976037). 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.*