# NM_001909.5(CTSD):c.952del (p.Val318fs)

https://sugi.bio/variant/ctsd-p-val318fs

## Summary

**CTSD p.Val318fs (c.952del)** is classified **Pathogenic/Likely pathogenic** in CTSD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00017%, nfe); Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs774781089 · 2 submitters · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the CTSD gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to neuronal ceroid lipofuscinosis.

*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 | 7 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010739/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTSD](https://sugi.bio/atlas/gene/CTSD/) |
| Protein change (HGVS p.) | p.Val318fs |
| Coding change (HGVS c.) | c.952del |
| MANE Select transcript | [NM_001909](https://www.ncbi.nlm.nih.gov/nuccore/NM_001909) |
| dbSNP | [rs774781089](https://www.ncbi.nlm.nih.gov/snp/rs774781089/) |
| Variant type | Deletion |
| Location | chr11:1754014-1754014 (GRCh38) |
| ClinVar | [VCV2145840](https://www.ncbi.nlm.nih.gov/clinvar/variation/2145840/) |

**All HGVS expressions:** `NC_000011.10:g.1754014del`, `NC_000011.9:g.1775244del`, `NG_008655.1:g.14979del`, `NM_001909.4:c.952del`, `NM_001909.5:c.952del`

## 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 5.873, phastCons 0.642 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.886, pLI 1.4812e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,176,854 in the highest group · 3/1,452,840 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00167% | 59,992 |
| European (non-Finnish) (grpmax) | 0.00017% | 588,426 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CTSD** population constraint: LOEUF 0.886, pLI 1.4812e-06, missense-Z 1.2419. *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):

- **neuronal ceroid lipofuscinosis** — Definitive (AR)

## Protein context {#protein}

Residue **318** lies in the peptidase a1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 85.69, 63% of residues very-high.

**9 experimental structure(s)** (PDB): [1LYA](https://www.rcsb.org/structure/1LYA), [1LYB](https://www.rcsb.org/structure/1LYB), [1LYW](https://www.rcsb.org/structure/1LYW), [4OBZ](https://www.rcsb.org/structure/4OBZ), [4OC6](https://www.rcsb.org/structure/4OC6), [4OD9](https://www.rcsb.org/structure/4OD9).

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

*Describes the biological roles of CTSD (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:** CTSD's established molecular role includes peptidase activity. p.Val318fs falls in the peptidase a1 domain.


### Pathways affected {#pathways}

CTSD participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Insulin receptor recycling](https://reactome.org/content/detail/R-HSA-77387) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Metabolism of Angiotensinogen to Angiotensins](https://reactome.org/content/detail/R-HSA-2022377) | 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:** peptidase activity.

**Biological process:** proteolysis, lipoprotein catabolic process, positive regulation of apoptotic process, regulation of establishment of protein localization, execution phase of apoptosis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2025–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-08 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-28 |

## Associated conditions {#conditions}

[neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis/).

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis, not provided, none provided, Neuronal Ceroid Lipofuscinoses.

## Similar variants {#similar}

Related CTSD variant pages (same residue, condition, or type): [CTSD p.Val318Met](/variant/ctsd-p-val318met), [CTSD p.Gln90fs](/variant/ctsd-p-gln90fs), [CTSD p.Val52fs](/variant/ctsd-p-val52fs), [CTSD p.Pro381fs](/variant/ctsd-p-pro381fs), [CTSD c.828-14_828-13del](/variant/ctsd-c-828-minus-14-828-minus-13del), [CTSD c.824_827+30del](/variant/ctsd-c-824-827-plus-30del), [CTSD p.Ala18fs](/variant/ctsd-p-ala18fs), [CTSD p.Ala317fs](/variant/ctsd-p-ala317fs).

### 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 2145840). 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.*