# NM_001372051.1(CASP8):c.99G>T (p.Arg33Ser)

https://sugi.bio/variant/casp8-p-arg33ser

## Summary

**CASP8 p.Arg33Ser (c.99G>T)** is classified **Uncertain significance** in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely pathogenic (0.7233); Very rare (popmax 0.00934%, afr); Associated with autoimmune lymphoproliferative syndrome type 2B.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs138862018 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00934%, afr)

## For patients & families {#patients}

This is a change in the CASP8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autoimmune lymphoproliferative syndrome type 2B.

*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 recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | CASP8 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009796/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CASP8](https://sugi.bio/atlas/gene/CASP8/) |
| Protein change (HGVS p.) | p.Arg33Ser |
| Coding change (HGVS c.) | c.99G>T |
| MANE Select transcript | [NM_001372051](https://www.ncbi.nlm.nih.gov/nuccore/NM_001372051) |
| dbSNP | [rs138862018](https://www.ncbi.nlm.nih.gov/snp/rs138862018/) |
| Variant type | single nucleotide variant |
| Location | chr2:201266585-201266585 (GRCh38) |
| ClinVar | [VCV2081380](https://www.ncbi.nlm.nih.gov/clinvar/variation/2081380/) |

**All HGVS expressions:** `LRG_34:g.38128G>T`, `LRG_34t1:c.99G>T`, `LRG_34t2:c.99G>T`, `LRG_34t3:c.99G>T`, `NC_000002.11:g.202131308G>T`, `NC_000002.12:g.201266585G>T`, `NG_007497.1:g.38128G>T`, `NM_001080124.2:c.99G>T`, `NM_001080125.2:c.276G>T`, `NM_001228.5:c.99G>T`, `NM_001372051.1:c.99G>T`, `NM_001400642.1:c.276G>T`, `NM_001400645.1:c.99G>T`, `NM_001400648.1:c.99G>T`, `NM_001400651.1:c.99G>T`, `NM_001400653.1:c.99G>T`, `NM_001400654.1:c.99G>T`, `NM_001400655.1:c.99G>T`, `NM_001400656.1:c.99G>T`, `NM_001400657.1:c.99G>T`, `NM_001400658.1:c.99G>T`, `NM_001400659.1:c.99G>T`, `NM_001400660.1:c.99G>T`, `NM_001400661.1:c.99G>T`, `NM_001400662.1:c.99G>T`, `NM_001400663.1:c.99G>T`, `NM_001400664.1:c.99G>T`, `NM_001400665.1:c.276G>T`, `NM_001400666.1:c.99G>T`, `NM_001400667.1:c.99G>T`, `NM_001400668.1:c.99G>T`, `NM_001400669.1:c.-4-4931G>T`, `NM_001400670.1:c.99G>T`, `NM_001400671.1:c.-434G>T`, `NM_001400672.1:c.-227-4931G>T`, `NM_001400673.1:c.-434G>T`, `NM_001400674.1:c.-615G>T`, `NM_001400675.1:c.-227-4931G>T`, `NM_001400676.1:c.-434G>T`, `NM_001400677.1:c.-434G>T`, `NM_001400678.1:c.-434G>T`, `NM_001400679.1:c.99G>T`, `NM_001400680.1:c.-513G>T`, `NM_001400750.1:c.-434G>T`, `NM_001400751.1:c.-434G>T`, `NM_033355.4:c.99G>T`, `NM_033356.4:c.99G>T`, `NR_111983.2:n.473G>T`, `NR_174564.1:n.203G>T`, `NR_174565.1:n.288G>T`, `NR_174581.1:n.314G>T`, `NR_174583.1:n.314G>T`, `NR_174584.1:n.473G>T`, `NR_174585.1:n.245G>T`, `NR_174586.1:n.219G>T`, `NR_174588.1:n.382G>T`, `NR_174589.1:n.177G>T`, `NR_174590.1:n.314G>T`, `NR_174591.1:n.245G>T`, `NR_174592.1:n.447G>T`, `NR_174593.1:n.245G>T`, `NR_174594.1:n.288G>T`, `NR_174595.1:n.203G>T`, `NR_174596.1:n.203G>T`, `NR_174597.1:n.203G>T`, `NR_174598.1:n.382G>T`, `NR_174599.1:n.203G>T`, `NR_174600.1:n.473G>T`, `NR_174601.1:n.219G>T`, `NR_174602.1:n.203G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7233)
- REVEL 0.292 (indeterminate)
- SaProt LLR -8.369 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.797, GERP -0.217, phastCons 0.999 — highly conserved (agrees)
- CADD: **PHRED 21.4**. 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 0.82** across the covering region of the MANE Select transcript (201,266,487–201,286,591), spanning 20,104 bp. Chi-square p 2.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.10**, donor gain **0.37**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.10**, donor gain **0.37**.
- Pangolin: Δ**0.27** (gain), gain 0.27 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00934%** (afr) · FAF95 0.00437% · FAF99 0.00309% · 7/74,928 in the highest group · 8/1,614,082 alleles overall — very rare (popmax 0.00934%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00934% | 10,704 |
| Admixed American | 0.00167% | 60,006 |

*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}

**CASP8** population constraint: LOEUF 0.695, pLI 0.012509, missense-Z 1.6719. *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):

- **autoimmune lymphoproliferative syndrome type 2B** — Definitive (AR)

## Protein context {#protein}

Residue **33** lies in the ded 1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.37, 49% of residues very-high.

**36 experimental structure(s)** (PDB): [1F9E](https://www.rcsb.org/structure/1F9E), [1I4E](https://www.rcsb.org/structure/1I4E), [1QDU](https://www.rcsb.org/structure/1QDU), [1QTN](https://www.rcsb.org/structure/1QTN), [2C2Z](https://www.rcsb.org/structure/2C2Z), [2FUN](https://www.rcsb.org/structure/2FUN).

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

*Describes the biological roles of CASP8 (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:** CASP8's established molecular role includes cysteine-type endopeptidase activity. p.Arg33Ser falls in the ded 1 domain. In Reactome, CASP8 is annotated in disease pathway(s) including **Defective RIPK1-mediated regulated necrosis**, **Microbial modulation of RIPK1-mediated regulated necrosis**.

**Disease mechanism (Reactome):** CASP8 loss or alteration is curated in [Defective RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9693928), [Microbial modulation of RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9686347).

### Pathways affected {#pathways}

CASP8 participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9693928) | other |
| ⚕ [Microbial modulation of RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9686347) | other |
| [Activation, myristolyation of BID and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-75108) | other |
| [Apoptotic cleavage of cellular proteins](https://reactome.org/content/detail/R-HSA-111465) | other |
| [Apoptotic execution phase](https://reactome.org/content/detail/R-HSA-75153) | other |
| [CASP8 activity is inhibited](https://reactome.org/content/detail/R-HSA-5218900) | other |
| [CLEC7A/inflammasome pathway](https://reactome.org/content/detail/R-HSA-5660668) | other |
| [Caspase activation via Death Receptors in the presence of ligand](https://reactome.org/content/detail/R-HSA-140534) | other |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | other |
| [Dimerization of procaspase-8](https://reactome.org/content/detail/R-HSA-69416) | other |
| [FasL/ CD95L signaling](https://reactome.org/content/detail/R-HSA-75157) | other |
| [NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10](https://reactome.org/content/detail/R-HSA-933543) | other |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | other |
| [RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-5213460) | other |
| [Regulation by c-FLIP](https://reactome.org/content/detail/R-HSA-3371378) | other |
| [Regulation of NF-kappa B signaling](https://reactome.org/content/detail/R-HSA-9758274) | other |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | other |
| [Regulation of necroptotic cell death](https://reactome.org/content/detail/R-HSA-5675482) | other |
| [TLR3-mediated TICAM1-dependent programmed cell death](https://reactome.org/content/detail/R-HSA-9013957) | other |
| [TNFR1-induced proapoptotic signaling](https://reactome.org/content/detail/R-HSA-5357786) | other |
| [TRAIL  signaling](https://reactome.org/content/detail/R-HSA-75158) | other |
| [TRIF-mediated programmed cell death](https://reactome.org/content/detail/R-HSA-2562578) | other |

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

**Molecular function:** cysteine-type endopeptidase activity, peptidase activity, ubiquitin protein ligase binding, death effector domain binding, identical protein binding, scaffold protein binding.

**Biological process:** proteolysis, apoptotic process, extrinsic apoptotic signaling pathway via death domain receptors, positive regulation of cell migration, positive regulation of interleukin-1 beta production, response to tumor necrosis factor.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-01 |

## Associated conditions {#conditions}

[autoimmune lymphoproliferative syndrome type 2B](https://sugi.bio/atlas/disease/autoimmune-lymphoproliferative-syndrome-type-2b/).

**Reported phenotype names (ClinVar):** Autoimmune lymphoproliferative syndrome type 2B, AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIB.

## Similar variants {#similar}

Related CASP8 variant pages (same residue, condition, or type): [CASP8 p.Arg248Trp](/variant/casp8-p-arg248trp), [CASP8 c.306-1926A>G](/variant/casp8-c-306-minus-1926a-g), [CASP8 c.306-1935G>A](/variant/casp8-c-306-minus-1935g-a), [CASP8 c.306-1971A>G](/variant/casp8-c-306-minus-1971a-g), [CASP8 c.660+6C>T](/variant/casp8-c-660-plus-6c-t), [CASP8 c.*107C>T](/variant/casp8-c-star-107c-t), [CASP8 p.Ala96Ser](/variant/casp8-p-ala96ser), [CASP8 p.Arg233Trp](/variant/casp8-p-arg233trp).

### 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 2081380). 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.*