# NM_001367721.1(CASK):c.1806G>A (p.Ser602=)

https://sugi.bio/variant/cask-p-ser602

## Summary

**CASK p.Ser602= (c.1806G>A)** is classified **Uncertain significance** in CASK (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-29). Very rare (popmax 0.00176%, sas); Associated with Intellectual disability, CASK-related, X-linked.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs780024880 · 2 submitters · 1 linked condition · very rare (popmax 0.00176%, sas)

## For patients & families {#patients}

This is a change in the CASK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Ser602= |
| Coding change (HGVS c.) | c.1806G>A |
| MANE Select transcript | [NM_001367721](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367721) |
| dbSNP | [rs780024880](https://www.ncbi.nlm.nih.gov/snp/rs780024880/) |
| Variant type | single nucleotide variant |
| Location | chrX:41557032-41557032 (GRCh38) |
| ClinVar | [VCV1970326](https://www.ncbi.nlm.nih.gov/clinvar/variation/1970326/) |

**All HGVS expressions:** `NC_000023.10:g.41416285C>T`, `NC_000023.11:g.41557032C>T`, `NG_016754.2:g.371003G>A`, `NM_001126054.3:c.1738-1397G>A`, `NM_001126055.3:c.1720-1397G>A`, `NM_001367721.1:c.1806G>A`, `NM_001410745.1:c.1788G>A`, `NM_003688.4:c.1806G>A`

## 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 loss** (Δ 0.91) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.644, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.91**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.91**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.74** (loss), gain 0.01 / loss 0.74. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00176%** (sas) · FAF95 3.7e-05% · FAF99 1.4e-05% · 1/56,856 in the highest group · 3/1,092,935 alleles overall — very rare (popmax 0.00176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00176% | 56,856 |
| European (non-Finnish) | 0.000225% | 445,351 |

*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 **602** lies in a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'required for interaction with nrxn1 (via c-terminal tail)' region; the 'disordered' 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.Ser602= falls in the required for interaction with nrxn1 (via c-terminal tail) region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-29 |

## 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, Nonpapillary renal cell carcinoma.

## Similar variants {#similar}

Related CASK variant pages (same residue, condition, or type): [CASK p.Ser602Leu](/variant/cask-p-ser602leu), [CASK p.Ser602Ala](/variant/cask-p-ser602ala), [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).

### 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 1970326). 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.*