# NM_001367721.1(CASK):c.54C>T (p.Ile18=)

https://sugi.bio/variant/cask-p-ile18

## Summary

**CASK p.Ile18= (c.54C>T)** is classified **Likely benign** in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-26). Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

**At a glance:** Likely benign · review: Single submitter · rsID rs2148116044 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CASK gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Intellectual disability, CASK-related, X-linked.

*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.Ile18= |
| Coding change (HGVS c.) | c.54C>T |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| dbSNP | [rs2148116044](https://www.ncbi.nlm.nih.gov/snp/rs2148116044/) |
| Variant type | single nucleotide variant |
| Location | chrX:41922935-41922935 (GRCh38) |
| ClinVar | [VCV1103806](https://www.ncbi.nlm.nih.gov/clinvar/variation/1103806/) |

**All HGVS expressions:** `NC_000023.10:g.41782188G>A`, `NC_000023.11:g.41922935G>A`, `NG_016754.2:g.5100C>T`, `NM_001126054.3:c.54C>T`, `NM_001126055.3:c.54C>T`, `NM_001367721.1:c.54C>T`, `NM_001410745.1:c.54C>T`, `NM_003688.4:c.54C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.614, GERP 2.93, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.66**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **18** lies in the protein kinase domain; a binding site; a β-strand.

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.Ile18= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-11-26.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-26 |

## Associated conditions {#conditions}

[Intellectual disability, CASK-related, X-linked](https://sugi.bio/atlas/disease/intellectual-disability-cask-related-x-linked/).

**Reported phenotype names (ClinVar):** Intellectual disability, CASK-related, X-linked.

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Arg489Gln](/variant/cask-p-arg489gln), [CASK p.Ala359Val](/variant/cask-p-ala359val), [CASK p.Ala833Thr](/variant/cask-p-ala833thr), [CASK p.Arg130Cys](/variant/cask-p-arg130cys), [CASK p.Arg572His](/variant/cask-p-arg572his), [CASK p.Arg61Trp](/variant/cask-p-arg61trp), [CASK p.Asp424Gly](/variant/cask-p-asp424gly), [CASK p.Asp445Asn](/variant/cask-p-asp445asn).

### 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 1103806). 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.*