# NM_001814.6(CTSC):c.1122del (p.Phe374fs)

https://sugi.bio/variant/ctsc-p-phe374fs

## Summary

**CTSC p.Phe374fs (c.1122del)** is classified **Pathogenic** in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). Very rare (popmax 8.47e-05%, nfe); Associated with periodontitis, aggressive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1944274161 · 1 submitter · 3 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CTSC gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to periodontitis, aggressive.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTSC](https://sugi.bio/atlas/gene/CTSC/) |
| Protein change (HGVS p.) | p.Phe374fs |
| Coding change (HGVS c.) | c.1122del |
| MANE Select transcript | [NM_001814](https://www.ncbi.nlm.nih.gov/nuccore/NM_001814) |
| dbSNP | [rs1944274161](https://www.ncbi.nlm.nih.gov/snp/rs1944274161/) |
| Variant type | Deletion |
| Location | chr11:88294276-88294276 (GRCh38) |
| ClinVar | [VCV2935808](https://www.ncbi.nlm.nih.gov/clinvar/variation/2935808/) |

**All HGVS expressions:** `LRG_50:g.48498del`, `LRG_50t1:c.1119del`, `NC_000011.10:g.88294279del`, `NC_000011.9:g.88027447del`, `NG_007952.1:g.48498del`, `NM_001814.6:c.1122del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.421, GERP 0.003, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.051, pLI 2.2986e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 25.4**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/152,100 alleles overall — very rare (popmax 8.47e-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}

**CTSC** population constraint: LOEUF 1.051, pLI 2.2986e-08, missense-Z -0.54589. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **374** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.64, 80% of residues very-high.

**18 experimental structure(s)** (PDB): [1K3B](https://www.rcsb.org/structure/1K3B), [2DJF](https://www.rcsb.org/structure/2DJF), [2DJG](https://www.rcsb.org/structure/2DJG), [3PDF](https://www.rcsb.org/structure/3PDF), [4CDC](https://www.rcsb.org/structure/4CDC), [4CDD](https://www.rcsb.org/structure/4CDD).

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

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


### Pathways affected {#pathways}

CTSC participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |

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

**Molecular function:** cysteine-type peptidase activity.

**Biological process:** proteolysis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-26.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-26 |

## Associated conditions {#conditions}

[periodontitis, aggressive](https://sugi.bio/atlas/disease/periodontitis-aggressive/), [Papillon-Lefevre disease](https://sugi.bio/atlas/disease/papillon-lefevre-disease/), [Haim-Munk syndrome](https://sugi.bio/atlas/disease/haim-munk-syndrome/).

**Reported phenotype names (ClinVar):** Periodontitis, aggressive, Haim-Munk syndrome, Papillon-Lefèvre syndrome, KERATOSIS PALMOPLANTARIS WITH PERIODONTOPATHIA, Papillon-Lefevre Disease, COCHIN JEWISH DISORDER, KERATOSIS PALMOPLANTARIS WITH PERIODONTOPATHIA AND ONYCHOGRYPOSIS.

## Similar variants {#similar}

Related CTSC variant pages (same residue, condition, or type): [CTSC p.Phe374Ser](/variant/ctsc-p-phe374ser), [CTSC p.Leu381fs](/variant/ctsc-p-leu381fs), [CTSC p.Lys63_Val64insTer](/variant/ctsc-p-lys63-val64inster), [CTSC p.Thr189fs](/variant/ctsc-p-thr189fs), [CTSC c.173-7del](/variant/ctsc-c-173-minus-7del), [CTSC c.486-25_492del](/variant/ctsc-c-486-minus-25-492del), [CTSC p.Ala417fs](/variant/ctsc-p-ala417fs), [CTSC p.Asp236fs](/variant/ctsc-p-asp236fs).

### 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 2935808). 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.*