# NM_001335.4(CTSW):c.190G>C (p.Asp64His)

https://sugi.bio/variant/ctsw-p-asp64his

## Summary

**CTSW p.Asp64His (c.190G>C)** is classified **Uncertain significance** in CTSW (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.1244); Very rare (popmax 0.00553%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs141204630 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00553%, nfe)

## For patients & families {#patients}

This is a change in the CTSW gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CTSW](https://sugi.bio/atlas/gene/CTSW/) |
| Protein change (HGVS p.) | p.Asp64His |
| Coding change (HGVS c.) | c.190G>C |
| MANE Select transcript | [NM_001335](https://www.ncbi.nlm.nih.gov/nuccore/NM_001335) |
| dbSNP | [rs141204630](https://www.ncbi.nlm.nih.gov/snp/rs141204630/) |
| Variant type | single nucleotide variant |
| Location | chr11:65881424-65881424 (GRCh38) |
| ClinVar | [VCV3078799](https://www.ncbi.nlm.nih.gov/clinvar/variation/3078799/) |

**All HGVS expressions:** `NC_000011.10:g.65881424G>C`, `NC_000011.9:g.65648895G>C`, `NM_001335.4:c.190G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1244)
- REVEL 0.317 (indeterminate)
- SaProt LLR -5.69 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.94, GERP -2.04, phastCons 0.302 — weakly conserved position
- CADD: **PHRED 15.1**. 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 0.99** across the covering region of the MANE Select transcript (65,879,855–65,883,615), spanning 3,760 bp. Chi-square p 0.82. 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 (G>T, Δ0.25 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.*
- Pangolin: Δ**0.26** (loss), gain 0.14 / loss 0.26. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00553%** (nfe) · FAF95 0.00445% · FAF99 0.00405% · 65/1,175,192 in the highest group · 68/1,604,952 alleles overall — very rare (popmax 0.00553%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00553% | 18,080 |
| Remaining individuals (not grpmax-eligible) | 0.00483% | 20,724 |

*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}

**CTSW** population constraint: LOEUF 1.135, pLI 1.5025e-12, missense-Z 0.43416. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.28, 69% of residues very-high.

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

*Describes the biological roles of CTSW (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.*


### Pathways affected {#pathways}

CTSW participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-29 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CTSW variant pages (same residue, condition, or type): [CTSW p.Ala109Gly](/variant/ctsw-p-ala109gly), [CTSW p.Ala140Thr](/variant/ctsw-p-ala140thr), [CTSW p.Ala28Val](/variant/ctsw-p-ala28val), [CTSW p.Ala41Asp](/variant/ctsw-p-ala41asp), [CTSW p.Ala41Thr](/variant/ctsw-p-ala41thr), [CTSW p.Ala71Thr](/variant/ctsw-p-ala71thr), [CTSW p.Arg107Lys](/variant/ctsw-p-arg107lys), [CTSW p.Arg135Gln](/variant/ctsw-p-arg135gln).

### 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 3078799). 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.*