# NM_001814.6(CTSC):c.1A>G (p.Met1Val)

https://sugi.bio/variant/ctsc-p-met1val

## Summary

**CTSC p.Met1Val (c.1A>G)** is classified **Conflicting classifications of pathogenicity** in CTSC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-20). Very rare (popmax 0.000259%, nfe); Associated with Papillon-Lefevre disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886048742 · 2 submitters · 3 linked conditions · very rare (popmax 0.000259%, nfe)

## For patients & families {#patients}

This is a change in the CTSC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Papillon-Lefevre disease.

*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, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CTSC is a diagnostic-grade gene on 11 Genomics England panels |

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

- Abnormality of the dentition — Very frequent (99-80%)
- Severe periodontitis — Very frequent (99-80%)
- Gingivitis — Very frequent (99-80%)
- Periodontitis — Very frequent (99-80%)
- Palmoplantar hyperkeratosis — Very frequent (99-80%)
- Palmoplantar keratoderma — Very frequent (99-80%)
- Abnormal fingernail morphology — Very frequent (99-80%)
- Atrophy of alveolar ridges — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003100/index) · [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.Met1Val |
| Coding change (HGVS c.) | c.1A>G |
| MANE Select transcript | [NM_001814](https://www.ncbi.nlm.nih.gov/nuccore/NM_001814) |
| dbSNP | [rs886048742](https://www.ncbi.nlm.nih.gov/snp/rs886048742/) |
| Variant type | single nucleotide variant |
| Location | chr11:88337672-88337672 (GRCh38) |
| ClinVar | [VCV306433](https://www.ncbi.nlm.nih.gov/clinvar/variation/306433/) |

**All HGVS expressions:** `LRG_50:g.5102A>G`, `LRG_50t1:c.1A>G`, `NC_000011.10:g.88337672T>C`, `NC_000011.9:g.88070840T>C`, `NG_007952.1:g.5102A>G`, `NM_001114173.3:c.1A>G`, `NM_001814.6:c.1A>G`, `NM_148170.5:c.1A>G`

## 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 5.712, GERP 0.2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **start-loss** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.051, pLI 2.2986e-08. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 19.99**. 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 **0.000259%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,158,632 in the highest group · 3/1,420,528 alleles overall — very rare (popmax 0.000259%, 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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-05-20.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Papillon-Lefèvre syndrome, Haim-Munk syndrome, Periodontitis, aggressive, 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 c.319-1G>A](/variant/ctsc-c-319-minus-1g-a), [CTSC c.757+1G>T](/variant/ctsc-c-757-plus-1g-t), [CTSC c.-55C>A](/variant/ctsc-c-minus-55c-a), [CTSC p.Arg210Ter](/variant/ctsc-p-arg210ter), [CTSC p.Arg250Ter](/variant/ctsc-p-arg250ter), [CTSC p.Arg272His](/variant/ctsc-p-arg272his), [CTSC p.Arg272Pro](/variant/ctsc-p-arg272pro), [CTSC p.Arg339Cys](/variant/ctsc-p-arg339cys).

### 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 306433). 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.*