# NM_001367721.1(CASK):c.497C>A (p.Ala166Asp)

https://sugi.bio/variant/cask-p-ala166asp

## Summary

**CASK p.Ala166Asp (c.497C>A)** is classified **Pathogenic** in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-12). AlphaMissense: likely pathogenic (0.9997); No allele count reported in gnomAD v4.1 (AN 1,203,743); Associated with Developmental disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2519234559 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,203,743)

## For patients & families {#patients}

This is a change in the CASK gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Developmental disorder.

*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 | [CASK](https://sugi.bio/atlas/gene/CASK/) |
| Protein change (HGVS p.) | p.Ala166Asp |
| Coding change (HGVS c.) | c.497C>A |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| dbSNP | [rs2519234559](https://www.ncbi.nlm.nih.gov/snp/rs2519234559/) |
| Variant type | single nucleotide variant |
| Location | chrX:41671463-41671463 (GRCh38) |
| ClinVar | [VCV2429864](https://www.ncbi.nlm.nih.gov/clinvar/variation/2429864/) |

**All HGVS expressions:** `NC_000023.10:g.41530716G>T`, `NC_000023.11:g.41671463G>T`, `NG_016754.2:g.256572C>A`, `NM_001126054.3:c.497C>A`, `NM_001126055.3:c.497C>A`, `NM_001367721.1:c.497C>A`, `NM_001410745.1:c.497C>A`, `NM_003688.4:c.497C>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9997) — concordant with the pathogenic call
- REVEL 0.895 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.636 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.806, GERP 1.58, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in CASK (of 5,480 modeled).
- CADD: **PHRED 29.6**. 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 0.31** across the covering region of the MANE Select transcript (41,636,647–41,922,988), spanning 286,341 bp — the region is depleted of missense variation. Chi-square p 1e-25. 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>C, Δ0.83 donor loss), 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: **no allele count reported in gnomAD v4.1 (AN 1,203,743)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}


Curated gene–disease validity (ClinGen):

- **X-linked syndromic intellectual disability** — Definitive (XL)

## Protein context {#protein}

Residue **166** lies in the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 79.45, 46% of residues very-high.

**22 experimental structure(s)** (PDB): [1KGD](https://www.rcsb.org/structure/1KGD), [1KWA](https://www.rcsb.org/structure/1KWA), [1ZL8](https://www.rcsb.org/structure/1ZL8), [3C0G](https://www.rcsb.org/structure/3C0G), [3C0H](https://www.rcsb.org/structure/3C0H), [3C0I](https://www.rcsb.org/structure/3C0I).

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

*Describes the biological roles of CASK (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:** CASK's established molecular role includes protein serine/threonine kinase activity. p.Ala166Asp falls in the protein kinase domain.


### Pathways affected {#pathways}

CASK participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-212676) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity.

**Biological process:** negative regulation of cell-matrix adhesion, negative regulation of keratinocyte proliferation, negative regulation of wound healing, negative regulation of cellular response to growth factor stimulus.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-03-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-12 |

## Associated conditions {#conditions}

[Developmental disorder](https://sugi.bio/atlas/disease/developmental-disorder/).

**Reported phenotype names (ClinVar):** Developmental disorder.

## Same-residue context {#hotspot}

Residue **166** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CASK p.Ala166Pro](/variant/cask-p-ala166pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Ala166Pro](/variant/cask-p-ala166pro), [CASK c.2317+5G>A](/variant/cask-c-2317-plus-5g-a), [CASK p.Lys665Arg](/variant/cask-p-lys665arg), [CASK p.Ile265fs](/variant/cask-p-ile265fs), [CASK c.1015+1G>A](/variant/cask-c-1015-plus-1g-a), [CASK c.1315-1G>A](/variant/cask-c-1315-minus-1g-a), [CASK c.2317+1G>A](/variant/cask-c-2317-plus-1g-a), [CASK c.2521-2A>G](/variant/cask-c-2521-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2429864). 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.*