# NM_001257118.3(CASP1):c.868C>T (p.Pro290Ser)

https://sugi.bio/variant/casp1-p-pro290ser

## Summary

**CASP1 p.Pro290Ser (c.868C>T)** is classified **Uncertain significance** in CASP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1126); Very rare (popmax 0.00017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the CASP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CASP1](https://sugi.bio/atlas/gene/CASP1/) |
| Protein change (HGVS p.) | p.Pro290Ser |
| Coding change (HGVS c.) | c.868C>T |
| MANE Select transcript | [NM_001257118](https://www.ncbi.nlm.nih.gov/nuccore/NM_001257118) |
| Variant type | single nucleotide variant |
| Location | chr11:105029262-105029262 (GRCh38) |
| ClinVar | [VCV4219354](https://www.ncbi.nlm.nih.gov/clinvar/variation/4219354/) |

**All HGVS expressions:** `NC_000011.10:g.105029262G>A`, `NC_000011.9:g.104899989G>A`, `NG_029124.2:g.10869C>T`, `NM_001223.5:c.805C>T`, `NM_001257118.3:c.868C>T`, `NM_001257119.3:c.805C>T`, `NM_033292.4:c.868C>T`, `NM_033293.4:c.589C>T`, `NM_033294.4:c.583+403C>T`, `NM_033295.4:c.59-2311C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1126)
- REVEL 0.003 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.12 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -2.107 — fast-evolving / accelerated position
- CADD: **PHRED 0.03**. 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 0.99** across the covering region of the MANE Select transcript (105,026,261–105,035,113), spanning 8,852 bp. Chi-square p 0.8. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.23 acceptor loss), 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,178,780 in the highest group · 4/1,610,222 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,145 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,390 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CASP1** population constraint: LOEUF 0.816, pLI 0.017654, missense-Z 0.47126. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.48, 58% of residues very-high.

**42 experimental structure(s)** (PDB): [1BMQ](https://www.rcsb.org/structure/1BMQ), [1IBC](https://www.rcsb.org/structure/1IBC), [1ICE](https://www.rcsb.org/structure/1ICE), [1RWK](https://www.rcsb.org/structure/1RWK), [1RWM](https://www.rcsb.org/structure/1RWM), [1RWN](https://www.rcsb.org/structure/1RWN) — incl. mutant structure 1SC1.

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

*Describes the biological roles of CASP1 (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:** CASP1's established molecular role includes endopeptidase activity. In Reactome, CASP1 is annotated in disease pathway(s) including **Purinergic signaling in leishmaniasis infection**, **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** CASP1 loss or alteration is curated in [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826), [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

CASP1 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Interleukin-1 processing](https://reactome.org/content/detail/R-HSA-448706) | curated |
| [Interleukin-37 signaling](https://reactome.org/content/detail/R-HSA-9008059) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [Regulation of GBP-mediated host defense](https://reactome.org/content/detail/R-HSA-9968551) | curated |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | curated |
| [The IPAF inflammasome](https://reactome.org/content/detail/R-HSA-844623) | curated |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | curated |
| [The AIM2 inflammasome](https://reactome.org/content/detail/R-HSA-844615) | electronic |

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

**Molecular function:** endopeptidase activity, cysteine-type endopeptidase activity, kinase binding, cytokine binding, identical protein binding, CARD domain binding.

**Biological process:** proteolysis, protein autoprocessing, positive regulation of interleukin-1 beta production, positive regulation of interleukin-18 production, positive regulation of canonical NF-kappaB signal transduction, regulation of inflammatory response.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-25 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CASP1 variant pages (same residue, condition, or type): [CASP1 p.Arg143=](/variant/casp1-p-arg143), [CASP1 p.Ile328=](/variant/casp1-p-ile328), [CASP1 p.Lys37Gln](/variant/casp1-p-lys37gln), [CASP1 p.Ala141Gly](/variant/casp1-p-ala141gly), [CASP1 p.Ala141Thr](/variant/casp1-p-ala141thr), [CASP1 p.Ala217Ser](/variant/casp1-p-ala217ser), [CASP1 p.Ala84Ser](/variant/casp1-p-ala84ser), [CASP1 p.Arg15Cys](/variant/casp1-p-arg15cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4219354). 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.*