# NM_001909.5(CTSD):c.231C>T (p.Ala77=)

https://sugi.bio/variant/ctsd-p-ala77

## Summary

**CTSD p.Ala77= (c.231C>T)** is classified **Benign** in CTSD (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Benign · review: Multiple submitters · rsID rs2230067 · 12 submitters · 2 linked conditions · common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CTSD gene that is classified as benign — not considered disease-causing, submitted by 12 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.Ala77= |
| Coding change (HGVS c.) | c.231C>T |
| MANE Select transcript | [NM_001909](https://www.ncbi.nlm.nih.gov/nuccore/NM_001909) |
| dbSNP | [rs2230067](https://www.ncbi.nlm.nih.gov/snp/rs2230067/) |
| Variant type | single nucleotide variant |
| Location | chr11:1759637-1759637 (GRCh38) |
| ClinVar | [VCV128875](https://www.ncbi.nlm.nih.gov/clinvar/variation/128875/) |

**All HGVS expressions:** `NC_000011.10:g.1759637G>A`, `NC_000011.9:g.1780867G>A`, `NG_008655.1:g.9356C>T`, `NM_001909.5:c.231C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 1.863, GERP -3.68, phastCons 1 — weakly conserved position
- CADD: **PHRED 14.72**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, 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 **12.5%** (mid) · FAF95 11.7% · FAF99 11.5% · 754/6,038 in the highest group · 125,861/1,612,446 alleles overall — common (popmax 12.5%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 12.5% | 8 |
| South Asian | 9.48% | 11 |
| Ashkenazi Jewish (not grpmax-eligible) | 8.84% | 11 |
| European (non-Finnish) | 8.4% | 12 |
| Remaining individuals (not grpmax-eligible) | 8.08% | 12 |
| Admixed American | 5.35% | 19 |
| Finnish (not grpmax-eligible) | 5.05% | 20 |
| African / African-American | 2.94% | 34 |
| East Asian | 2.5% | 40 |
| Amish (not grpmax-eligible) | 2.3% | 43 |

*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 **77** lies in a turn.

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.


### 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (11 Benign, 1 Likely benign).

**Submission history:** 12 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-05-26 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-05-07 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | criteria provided, single submitter | clinical testing | 2015-09-21 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing | 2017-09-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2015-10-26 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-03-14 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis/), [neuronal ceroid lipofuscinosis 10](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis-10/).

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis, not specified, not provided, Neuronal ceroid lipofuscinosis 10, Inborn genetic diseases, AllHighlyPenetrant, Neuronal Ceroid Lipofuscinoses, none provided, NEURONAL CEROID LIPOFUSCINOSIS DUE TO CATHEPSIN D DEFICIENCY, CTSD-Related Neuronal Ceroid-Lipofuscinosis.

## Similar variants {#similar}

Related CTSD variant pages (same residue, condition, or type): [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 c.*210C>G](/variant/ctsd-c-star-210c-g), [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 128875). 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.*