# NM_001909.5(CTSD):c.571A>G (p.Ile191Val)

https://sugi.bio/variant/ctsd-p-ile191val

## Summary

**CTSD p.Ile191Val (c.571A>G)** is classified **Uncertain significance** in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.01%, amr); Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750166391 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.01%, amr)

## 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.Ile191Val |
| Coding change (HGVS c.) | c.571A>G |
| MANE Select transcript | [NM_001909](https://www.ncbi.nlm.nih.gov/nuccore/NM_001909) |
| dbSNP | [rs750166391](https://www.ncbi.nlm.nih.gov/snp/rs750166391/) |
| Variant type | single nucleotide variant |
| Location | chr11:1757457-1757457 (GRCh38) |
| ClinVar | [VCV1424032](https://www.ncbi.nlm.nih.gov/clinvar/variation/1424032/) |

**All HGVS expressions:** `NC_000011.10:g.1757457T>C`, `NC_000011.9:g.1778687T>C`, `NG_008655.1:g.11536A>G`, `NM_001909.5:c.571A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0837)
- REVEL 0.063 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.846 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.595, GERP -2.89, phastCons 1 — weakly conserved position
- CADD: **PHRED 13.73**. 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 0.87** across the covering region of the MANE Select transcript (1,753,506–1,763,859), spanning 10,353 bp. Chi-square p 0.0029. 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 (T>A, Δ0.32 acceptor gain), 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 **0.01%** (amr) · FAF95 0.00428% · FAF99 0.00295% · 6/60,022 in the highest group · 6/1,461,764 alleles overall — very rare (popmax 0.01%, amr).

*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 **191** lies in a turn; 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.Ile191Val 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 2024-10-24.

**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 | 2024-10-24 |

## 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.Ile191=](/variant/ctsd-p-ile191), [CTSD c.228+1G>A](/variant/ctsd-c-228-plus-1g-a), [CTSD p.Glu82Ter](/variant/ctsd-p-glu82ter), [CTSD c.828-3C>A](/variant/ctsd-c-828-minus-3c-a), [CTSD p.Ala10Ser](/variant/ctsd-p-ala10ser), [CTSD p.Ala18Pro](/variant/ctsd-p-ala18pro), [CTSD p.Ala18Thr](/variant/ctsd-p-ala18thr), [CTSD p.Ala239Val](/variant/ctsd-p-ala239val).

### 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 1424032). 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.*