# NM_001226.4(CASP6):c.97C>T (p.Pro33Ser)

https://sugi.bio/variant/casp6-p-pro33ser

## Summary

**CASP6 p.Pro33Ser (c.97C>T)** is classified **Uncertain significance** in CASP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1489); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CASP6 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 | [CASP6](https://sugi.bio/atlas/gene/CASP6/) |
| Protein change (HGVS p.) | p.Pro33Ser |
| Coding change (HGVS c.) | c.97C>T |
| MANE Select transcript | [NM_001226](https://www.ncbi.nlm.nih.gov/nuccore/NM_001226) |
| Variant type | single nucleotide variant |
| Location | chr4:109697755-109697755 (GRCh38) |
| ClinVar | [VCV4219404](https://www.ncbi.nlm.nih.gov/clinvar/variation/4219404/) |

**All HGVS expressions:** `NC_000004.11:g.110618911G>A`, `NC_000004.12:g.109697755G>A`, `NG_029187.1:g.10719C>T`, `NG_029187.2:g.17012C>T`, `NM_001226.4:c.97C>T`, `NM_032992.3:c.41-3055C>T`, `NR_133012.2:n.147C>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** (0.1489)
- REVEL 0.295 (indeterminate)
- SaProt LLR -5.039 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 9.782, GERP 1.96, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.6**. 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 0.91** across the covering region of the MANE Select transcript (109,689,333–109,703,395), spanning 14,062 bp. Chi-square p 0.082. 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, Δ0.21 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 **8.48e-05%** (nfe) · 1/1,179,540 in the highest group · 1/1,460,412 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**CASP6** population constraint: LOEUF 0.953, pLI 7.9741e-05, missense-Z 0.75485. *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 85.54, 67% of residues very-high.

**37 experimental structure(s)** (PDB): [2WDP](https://www.rcsb.org/structure/2WDP), [3K7E](https://www.rcsb.org/structure/3K7E), [3NKF](https://www.rcsb.org/structure/3NKF), [3NR2](https://www.rcsb.org/structure/3NR2), [3OD5](https://www.rcsb.org/structure/3OD5), [3P45](https://www.rcsb.org/structure/3P45).

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

*Describes the biological roles of CASP6 (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:** CASP6's established molecular role includes cysteine-type endopeptidase activity.


### Pathways affected {#pathways}

CASP6 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Apoptotic cleavage of cellular proteins](https://reactome.org/content/detail/R-HSA-111465) | curated |
| [Breakdown of the nuclear lamina](https://reactome.org/content/detail/R-HSA-352238) | other |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | other |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | other |

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

**Molecular function:** cysteine-type endopeptidase activity, identical protein binding.

**Biological process:** activation of innate immune response, proteolysis, protein autoprocessing, epithelial cell differentiation, positive regulation of apoptotic process, regulation of programmed cell death.

## 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 CASP6 variant pages (same residue, condition, or type): [CASP6 p.Ala129Val](/variant/casp6-p-ala129val), [CASP6 p.Ala194Gly](/variant/casp6-p-ala194gly), [CASP6 p.Arg164Gln](/variant/casp6-p-arg164gln), [CASP6 p.Arg220Gln](/variant/casp6-p-arg220gln), [CASP6 p.Arg260Gln](/variant/casp6-p-arg260gln), [CASP6 p.Arg76Cys](/variant/casp6-p-arg76cys), [CASP6 p.Arg76Gly](/variant/casp6-p-arg76gly), [CASP6 p.Arg76His](/variant/casp6-p-arg76his).

### 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 4219404). 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.*