# NM_003011.4(SET):c.452del (p.Pro151fs)

https://sugi.bio/variant/set-p-pro151fs

## Summary

**SET p.Pro151fs (c.452del)** is classified **Pathogenic** in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-15). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2490437438 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SET gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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 | [SET](https://sugi.bio/atlas/gene/SET/) |
| Protein change (HGVS p.) | p.Pro151fs |
| Coding change (HGVS c.) | c.452del |
| MANE Select transcript | [NM_003011](https://www.ncbi.nlm.nih.gov/nuccore/NM_003011) |
| dbSNP | [rs2490437438](https://www.ncbi.nlm.nih.gov/snp/rs2490437438/) |
| Variant type | Deletion |
| Location | chr9:128692940-128692940 (GRCh38) |
| ClinVar | [VCV3160560](https://www.ncbi.nlm.nih.gov/clinvar/variation/3160560/) |

**All HGVS expressions:** `NC_000009.11:g.131455220del`, `NC_000009.12:g.128692941del`, `NG_030356.1:g.14287del`, `NM_001122821.2:c.491del`, `NM_001248000.2:c.425del`, `NM_001248001.2:c.419del`, `NM_001374326.1:c.491del`, `NM_003011.4:c.452del`

## 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 1.139, GERP 2.04, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.167, pLI 0.99973), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 8**, 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}

**SET** population constraint: LOEUF 0.167, pLI 0.99973, missense-Z 3.2081; 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):

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

## Protein context {#protein}

Residue **151** lies in a β-strand; the 'earmuff domain' region.

AlphaFold model confidence (whole protein): pLDDT 78.62, 58% of residues very-high.

**3 experimental structure(s)** (PDB): [2E50](https://www.rcsb.org/structure/2E50), [7MTO](https://www.rcsb.org/structure/7MTO), [9I15](https://www.rcsb.org/structure/9I15).

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

*Describes the biological roles of SET (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.*


### Pathways affected {#pathways}

SET participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | curated |
| [HuR (ELAVL1) binds and stabilizes mRNA](https://reactome.org/content/detail/R-HSA-450520) | curated |

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

**Biological process:** negative regulation of neuron apoptotic process, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-15 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related SET variant pages (same residue, condition, or type): [SET p.Gly200fs](/variant/set-p-gly200fs), [SET p.Gly232del](/variant/set-p-gly232del), [SET p.Asp260Glu](/variant/set-p-asp260glu), [SET p.Glu261Asp](/variant/set-p-glu261asp), [SET p.Asp235Glu](/variant/set-p-asp235glu), [SET p.Asp264del](/variant/set-p-asp264del), [SET c.492+4T>C](/variant/set-c-492-plus-4t-c), [SET p.Glu233Gly](/variant/set-p-glu233gly).

### 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 3160560). 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.*