# NM_001367721.1(CASK):c.396C>A (p.Cys132Ter)

https://sugi.bio/variant/cask-p-cys132ter

## Summary

**CASK p.Cys132Ter (c.396C>A)** is classified **Likely pathogenic** in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-16). No allele count reported in gnomAD v4.1 (AN 1,185,346); Associated with syndromic X-linked intellectual disability Najm type.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,185,346)

## For patients & families {#patients}

This is a change in the CASK gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to syndromic X-linked intellectual disability Najm type.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CASK is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of X-linked intellectual disability, Najm type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive microcephaly — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Intellectual disability, moderate — Very frequent (99-80%)
- Severe global developmental delay — Very frequent (99-80%)
- Hypoplasia of the pons — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Retrognathia — Frequent (79-30%)
- Hypertelorism — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012669/index) · [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.Cys132Ter |
| Coding change (HGVS c.) | c.396C>A |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| Variant type | single nucleotide variant |
| Location | chrX:41739417-41739417 (GRCh38) |
| ClinVar | [VCV4759222](https://www.ncbi.nlm.nih.gov/clinvar/variation/4759222/) |

**All HGVS expressions:** `NC_000023.10:g.41598670G>T`, `NC_000023.11:g.41739417G>T`, `NG_016754.2:g.188618C>A`, `NM_001126054.3:c.396C>A`, `NM_001126055.3:c.396C>A`, `NM_001367721.1:c.396C>A`, `NM_001410745.1:c.396C>A`, `NM_003688.4:c.396C>A`

## Computational & population evidence {#evidence}

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

- **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 3.496, GERP 0.823, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 27**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,185,346)** — 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 **132** lies in the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix.

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.Cys132Ter 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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ozbek Human Genetics Laboratory, Izmir Biomedicine and Genome Center | Likely pathogenic | criteria provided, single submitter | research | 2025-10-16 |

## Associated conditions {#conditions}

[syndromic X-linked intellectual disability Najm type](https://sugi.bio/atlas/disease/syndromic-x-linked-intellectual-disability-najm-type/).

**Reported phenotype names (ClinVar):** Syndromic X-linked intellectual disability Najm type, MICPCH SYNDROME, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia, Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, MENTAL RETARDATION, X-LINKED, SYNDROMIC, NAJM TYPE, Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH).

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [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.2317+5G>A](/variant/cask-c-2317-plus-5g-a), [CASK c.59+2T>C](/variant/cask-c-59-plus-2t-c), [CASK p.Arg106Ter](/variant/cask-p-arg106ter), [CASK p.Arg255Cys](/variant/cask-p-arg255cys), [CASK p.Arg27Ter](/variant/cask-p-arg27ter).

### 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 4759222). 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.*