# NM_001367721.1(CASK):c.1838del (p.Arg613fs)

https://sugi.bio/variant/cask-p-arg613fs

## Summary

**CASK p.Arg613fs (c.1838del)** is classified **Likely pathogenic** in CASK (ClinVar, Single submitter, 1 submitter). Associated with syndromic X-linked intellectual disability Najm type.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## 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.Arg613fs |
| Coding change (HGVS c.) | c.1838del |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| Variant type | Deletion |
| Location | chrX:41555604-41555604 (GRCh38) |
| ClinVar | [VCV4531271](https://www.ncbi.nlm.nih.gov/clinvar/variation/4531271/) |

**All HGVS expressions:** `NC_000023.10:g.41414857del`, `NC_000023.11:g.41555604del`, `NG_016754.2:g.372431del`, `NM_001126054.3:c.1769del`, `NM_001126055.3:c.1751del`, `NM_001367721.1:c.1838del`, `NM_001410745.1:c.1820del`, `NM_003688.4:c.1838del`

## 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 6.242, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 20 of 27**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **613** lies in a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region.

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.Arg613fs falls in the sh3 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)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## 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, MENTAL RETARDATION, X-LINKED, SYNDROMIC, NAJM TYPE, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia, Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH), MICPCH SYNDROME, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia.

## Same-residue context {#hotspot}

Residue **613** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CASK p.Arg613Ter](/variant/cask-p-arg613ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Arg613Ter](/variant/cask-p-arg613ter), [CASK p.Thr548fs](/variant/cask-p-thr548fs), [CASK p.Val292del](/variant/cask-p-val292del), [CASK c.116_117delCA](/variant/cask-c-116-117delca), [CASK c.173-1145_278+7387del](/variant/cask-c-173-minus-1145-278-plus-7387del), [CASK p.Asp98fs](/variant/cask-p-asp98fs), [CASK p.Cys205fs](/variant/cask-p-cys205fs), [CASK p.Ile649fs](/variant/cask-p-ile649fs).

### 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 4531271). 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.*