# NM_032977.4(CASP10):c.615C>T (p.Ala205=)

https://sugi.bio/variant/casp10-p-ala205

## Summary

**CASP10 p.Ala205= (c.615C>T)** is classified **Likely benign** in CASP10 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). Very rare (popmax 0.00549%, sas); Associated with autoimmune lymphoproliferative syndrome type 2A.

**At a glance:** Likely benign · review: Single submitter · rsID rs373077581 · 1 submitter · 1 linked condition · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the CASP10 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to autoimmune lymphoproliferative syndrome type 2A.

*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 |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | CASP10 is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Autoimmune lymphoproliferative syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Splenomegaly — Very frequent (99-80%)
- Lymphadenopathy — Very frequent (99-80%)
- Chronic noninfectious lymphadenopathy — Very frequent (99-80%)
- Autoimmunity — Very frequent (99-80%)
- Bruising susceptibility — Frequent (79-30%)
- Autoimmune hemolytic anemia — Frequent (79-30%)
- Abnormal bleeding — Frequent (79-30%)
- Neutropenia in presence of anti-neutropil antibodies — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015361/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CASP10](https://sugi.bio/atlas/gene/CASP10/) |
| Protein change (HGVS p.) | p.Ala205= |
| Coding change (HGVS c.) | c.615C>T |
| MANE Select transcript | [NM_032977](https://www.ncbi.nlm.nih.gov/nuccore/NM_032977) |
| dbSNP | [rs373077581](https://www.ncbi.nlm.nih.gov/snp/rs373077581/) |
| Variant type | single nucleotide variant |
| Location | chr2:201195879-201195879 (GRCh38) |
| ClinVar | [VCV2420373](https://www.ncbi.nlm.nih.gov/clinvar/variation/2420373/) |

**All HGVS expressions:** `LRG_33:g.17748C>T`, `LRG_33t1:c.615C>T`, `NC_000002.11:g.202060602C>T`, `NC_000002.12:g.201195879C>T`, `NG_007265.1:g.17748C>T`, `NM_001206524.2:c.615C>T`, `NM_001206542.2:c.615C>T`, `NM_001230.5:c.615C>T`, `NM_001306083.2:c.615C>T`, `NM_032974.5:c.615C>T`, `NM_032976.4:c.615C>T`, `NM_032977.4:c.615C>T`

## 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 -4.741, GERP -2.16 — fast-evolving / accelerated position
- CADD: **PHRED 1.922**. 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.*
- 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 (gnomAD v4.1): grpmax **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,064 in the highest group · 19/1,613,664 alleles overall — very rare (popmax 0.00549%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00549% | 18,213 |
| East Asian | 0.00223% | 44,888 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,478 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,986 |
| European (non-Finnish) | 0.000932% | 107,258 |

*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}

**CASP10** population constraint: LOEUF 1.046, pLI 6.3858e-09, missense-Z 0.61351; ClinGen dosage — haploinsufficiency 1, 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):

- **autoimmune lymphoproliferative syndrome type 2A** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.54, 42% of residues very-high.

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

*Describes the biological roles of CASP10 (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:** CASP10's established molecular role includes cysteine-type endopeptidase activity.


### Pathways affected {#pathways}

CASP10 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [FasL/ CD95L signaling](https://reactome.org/content/detail/R-HSA-75157) | curated |
| [NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10](https://reactome.org/content/detail/R-HSA-933543) | curated |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | curated |
| [TRAIL  signaling](https://reactome.org/content/detail/R-HSA-75158) | curated |

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

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

**Biological process:** positive regulation of canonical NF-kappaB signal transduction, protein maturation, positive regulation of execution phase of apoptosis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-08 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Autoimmune lymphoproliferative syndrome type 2A, Autoimmune lymphoproliferative syndrome type 2, CASP10-Related Autoimmune Lymphoproliferative Syndrome, AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA.

## Similar variants {#similar}

Related CASP10 variant pages (same residue, condition, or type): [CASP10 c.1415+2T>C](/variant/casp10-c-1415-plus-2t-c), [CASP10 c.1416-3C>A](/variant/casp10-c-1416-minus-3c-a), [CASP10 c.347+2T>G](/variant/casp10-c-347-plus-2t-g), [CASP10 c.684+1G>A](/variant/casp10-c-684-plus-1g-a), [CASP10 c.922+5G>A](/variant/casp10-c-922-plus-5g-a), [CASP10 p.Ala237Glu](/variant/casp10-p-ala237glu), [CASP10 p.Ala248Val](/variant/casp10-p-ala248val), [CASP10 p.Ala259Thr](/variant/casp10-p-ala259thr).

### 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 2420373). 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.*