# NM_001909.5(CTSD):c.692_694del (p.Phe231del)

https://sugi.bio/variant/ctsd-p-phe231del

## Summary

**CTSD p.Phe231del (c.692_694del)** is classified **Uncertain significance** in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10). Very rare (popmax 0.00267%, afr); Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1478615059 · 1 submitter · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the CTSD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Phe231del |
| Coding change (HGVS c.) | c.692_694del |
| MANE Select transcript | [NM_001909](https://www.ncbi.nlm.nih.gov/nuccore/NM_001909) |
| dbSNP | [rs1478615059](https://www.ncbi.nlm.nih.gov/snp/rs1478615059/) |
| Variant type | Deletion |
| Location | chr11:1757334-1757336 (GRCh38) |
| ClinVar | [VCV1518691](https://www.ncbi.nlm.nih.gov/clinvar/variation/1518691/) |

**All HGVS expressions:** `NC_000011.10:g.1757336_1757338del`, `NC_000011.9:g.1778566_1778568del`, `NG_008655.1:g.11657_11659del`, `NM_001909.5:c.692_694del`

## 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 2.292, GERP 1.67, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 20.3**. 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,920 in the highest group · 5/1,613,308 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,460 |
| Admixed American | 0.00167% | 59,982 |
| European (non-Finnish) | 0.00017% | 589,842 |

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

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.Phe231del 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis, Neuronal Ceroid Lipofuscinoses.

## Similar variants {#similar}

Related CTSD variant pages (same residue, condition, or type): [CTSD p.Phe231=](/variant/ctsd-p-phe231), [CTSD p.Gln90fs](/variant/ctsd-p-gln90fs), [CTSD p.Val318fs](/variant/ctsd-p-val318fs), [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).

### 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 1518691). 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.*