# NM_001372051.1(CASP8):c.386C>T (p.Ser129Phe)

https://sugi.bio/variant/casp8-p-ser129phe

## Summary

**CASP8 p.Ser129Phe (c.386C>T)** is classified **Uncertain significance** in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.2843); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2125234781 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## 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 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 | [CASP8](https://sugi.bio/atlas/gene/CASP8/) |
| Protein change (HGVS p.) | p.Ser129Phe |
| Coding change (HGVS c.) | c.386C>T |
| MANE Select transcript | [NM_001372051](https://www.ncbi.nlm.nih.gov/nuccore/NM_001372051) |
| dbSNP | [rs2125234781](https://www.ncbi.nlm.nih.gov/snp/rs2125234781/) |
| Variant type | single nucleotide variant |
| Location | chr2:201271596-201271596 (GRCh38) |
| ClinVar | [VCV3137626](https://www.ncbi.nlm.nih.gov/clinvar/variation/3137626/) |

**All HGVS expressions:** `LRG_34:g.43139C>T`, `LRG_34t1:c.482C>T`, `LRG_34t2:c.386C>T`, `LRG_34t3:c.386C>T`, `NC_000002.11:g.202136319C>T`, `NC_000002.12:g.201271596C>T`, `NG_007497.1:g.43139C>T`, `NM_001080124.2:c.386C>T`, `NM_001080125.2:c.563C>T`, `NM_001228.5:c.482C>T`, `NM_001372051.1:c.386C>T`, `NM_001400642.1:c.563C>T`, `NM_001400645.1:c.386C>T`, `NM_001400648.1:c.386C>T`, `NM_001400651.1:c.386C>T`, `NM_001400653.1:c.386C>T`, `NM_001400654.1:c.386C>T`, `NM_001400655.1:c.386C>T`, `NM_001400656.1:c.386C>T`, `NM_001400657.1:c.386C>T`, `NM_001400658.1:c.386C>T`, `NM_001400659.1:c.386C>T`, `NM_001400660.1:c.386C>T`, `NM_001400661.1:c.386C>T`, `NM_001400662.1:c.386C>T`, `NM_001400663.1:c.386C>T`, `NM_001400664.1:c.386C>T`, `NM_001400665.1:c.563C>T`, `NM_001400666.1:c.386C>T`, `NM_001400667.1:c.386C>T`, `NM_001400668.1:c.386C>T`, `NM_001400669.1:c.77C>T`, `NM_001400670.1:c.386C>T`, `NM_001400671.1:c.-147C>T`, `NM_001400672.1:c.-147C>T`, `NM_001400673.1:c.-147C>T`, `NM_001400674.1:c.-328C>T`, `NM_001400675.1:c.-147C>T`, `NM_001400676.1:c.-147C>T`, `NM_001400677.1:c.-147C>T`, `NM_001400678.1:c.-147C>T`, `NM_001400679.1:c.386C>T`, `NM_001400680.1:c.-226C>T`, `NM_001400750.1:c.-147C>T`, `NM_001400751.1:c.-147C>T`, `NM_033355.4:c.386C>T`, `NM_033356.4:c.386C>T`, `NR_111983.2:n.760C>T`, `NR_174583.1:n.601C>T`, `NR_174584.1:n.760C>T`, `NR_174585.1:n.532C>T`, `NR_174586.1:n.506C>T`, `NR_174588.1:n.669C>T`, `NR_174589.1:n.464C>T`, `NR_174590.1:n.601C>T`, `NR_174591.1:n.532C>T`, `NR_174592.1:n.734C>T`, `NR_174593.1:n.532C>T`, `NR_174594.1:n.575C>T`, `NR_174595.1:n.490C>T`, `NR_174596.1:n.490C>T`, `NR_174597.1:n.490C>T`, `NR_174598.1:n.669C>T`, `NR_174599.1:n.490C>T`, `NR_174600.1:n.760C>T`, `NR_174601.1:n.506C>T`, `NR_174602.1:n.490C>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** (0.2843)
- REVEL 0.255 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.958 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.904, GERP 1.56, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.1**. 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: **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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **129** lies in the ded 2 domain; a β-strand.

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.Ser129Phe falls in the ded 2 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 2024-01-30.

**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 | 2024-01-30 |

## 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 CASP8 variant pages (same residue, condition, or type): [CASP8 p.Ser129=](/variant/casp8-p-ser129), [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 p.Arg233Trp](/variant/casp8-p-arg233trp), [CASP8 p.Asp223Asn](/variant/casp8-p-asp223asn), [CASP8 p.Cys236Arg](/variant/casp8-p-cys236arg), [CASP8 p.Glu84Gly](/variant/casp8-p-glu84gly), [CASP8 p.Gly350Arg](/variant/casp8-p-gly350arg).

### 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 3137626). 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.*