# NM_001909.5(CTSD):c.75G>A (p.Pro25=)

https://sugi.bio/variant/ctsd-p-pro25

## Summary

**CTSD p.Pro25= (c.75G>A)** is classified **Conflicting classifications of pathogenicity** in CTSD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-02). Rare (popmax 0.168%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs140563067 · 6 submitters · 2 linked conditions · rare (popmax 0.168%, afr)

## For patients & families {#patients}

This is a change in the CTSD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Pro25= |
| Coding change (HGVS c.) | c.75G>A |
| dbSNP | [rs140563067](https://www.ncbi.nlm.nih.gov/snp/rs140563067/) |
| Variant type | single nucleotide variant |
| Location | chr11:1761462-1761462 (GRCh38) |
| ClinVar | [VCV195156](https://www.ncbi.nlm.nih.gov/clinvar/variation/195156/) |

**All HGVS expressions:** `NC_000011.10:g.1761462C>T`, `NC_000011.9:g.1782692C>T`, `NG_008655.1:g.7531G>A`, `NM_001909.5:c.75G>A`

## 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 -15.256, GERP -2.03 — fast-evolving / accelerated position
- CADD: **PHRED 0.298**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.168%** (afr) · FAF95 0.144% · FAF99 0.135% · 126/75,046 in the highest group · 147/1,613,810 alleles overall — rare (popmax 0.168%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.168% | 596 |
| Admixed American | 0.00666% | 15,006 |
| South Asian | 0.00439% | 22,769 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,247 |
| European (non-Finnish) | 0.000932% | 107,271 |

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-17 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-17 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-06-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Neuronal ceroid lipofuscinosis, CTSD-related disorder, not specified, CTSD-related condition, AllHighlyPenetrant, Neuronal Ceroid Lipofuscinoses, none provided.

### 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 195156). 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.*