# NM_001367721.1(CASK):c.1641_1644del (p.Thr548fs)

https://sugi.bio/variant/cask-p-thr548fs

## Summary

**CASK p.Thr548fs (c.1641_1644del)** is classified **Pathogenic/Likely pathogenic** in CASK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2022-05-22). No gnomAD frequency available for this variant; Associated with CASK-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1569306724 · 6 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CASK gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to CASK-related 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.Thr548fs |
| Coding change (HGVS c.) | c.1641_1644del |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| dbSNP | [rs1569306724](https://www.ncbi.nlm.nih.gov/snp/rs1569306724/) |
| Variant type | Deletion |
| Location | chrX:41561583-41561586 (GRCh38) |
| ClinVar | [VCV570810](https://www.ncbi.nlm.nih.gov/clinvar/variation/570810/) |

**All HGVS expressions:** `NC_000023.10:g.41420838_41420841del`, `NC_000023.11:g.41561585_41561588del`, `NG_016754.2:g.366449_366452del`, `NM_001126054.3:c.1639_1642delCAAA`, `NM_001126055.3:c.1621_1624delCAAA`, `NM_001367721.1:c.1641_1644del`, `NM_001367721.1:c.1641_1644delAACA`, `NM_001410745.1:c.1621_1624delCAAA`, `NM_003688.3:c.1641_1644delAACA`, `NM_003688.4:c.1639_1642delCAAA`

## 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 7.634, GERP 1.89, 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 17 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.
- Population frequency: **no gnomAD frequency available for this variant** — 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 **548** lies in a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the pdz 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.Thr548fs falls in the pdz 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-05-22.

**Submitter consensus:** conflicting (5 Pathogenic, 1 Likely pathogenic).

**Submission history:** 6 submissions (2020–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Pediatric Genetics Clinic, Sheba Medical Center | Pathogenic | no assertion criteria provided | clinical testing | 2021-05-13 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-22 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-18 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-02 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-06-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** CASK-related disorder, Intellectual disability, CASK-related, X-linked, not provided, Syndromic X-linked intellectual disability Najm type, CASK-related disorders, CASK-related condition, none provided, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, MENTAL RETARDATION, X-LINKED, SYNDROMIC, NAJM TYPE.

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Val292del](/variant/cask-p-val292del), [CASK c.116_117delCA](/variant/cask-c-116-117delca), [CASK c.1504-2_1504-1del](/variant/cask-c-1504-minus-2-1504-minus-1del), [CASK c.173-1145_278+7387del](/variant/cask-c-173-minus-1145-278-plus-7387del), [CASK p.Ala814fs](/variant/cask-p-ala814fs), [CASK p.Arg613fs](/variant/cask-p-arg613fs), [CASK p.Asp98fs](/variant/cask-p-asp98fs), [CASK p.Cys205fs](/variant/cask-p-cys205fs).

### 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 570810). 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.*