# NM_001367721.1(CASK):c.2668T>G (p.Phe890Val)

https://sugi.bio/variant/cask-p-phe890val

## Summary

**CASK p.Phe890Val (c.2668T>G)** is classified **Likely benign** in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-11). AlphaMissense: likely pathogenic (0.9645); Very rare (popmax 0.00351%, afr); Associated with Intellectual disability, CASK-related, X-linked.

**At a glance:** Likely benign · review: Single submitter · rsID rs947512647 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00351%, afr)

## 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.Phe890Val |
| Coding change (HGVS c.) | c.2668T>G |
| dbSNP | [rs947512647](https://www.ncbi.nlm.nih.gov/snp/rs947512647/) |
| Variant type | single nucleotide variant |
| Location | chrX:41520533-41520533 (GRCh38) |
| ClinVar | [VCV1919556](https://www.ncbi.nlm.nih.gov/clinvar/variation/1919556/) |

**All HGVS expressions:** `NC_000023.10:g.41379786A>C`, `NC_000023.11:g.41520533A>C`, `NG_016754.2:g.407502T>G`, `NM_001126054.3:c.2584T>G`, `NM_001126055.3:c.2581T>G`, `NM_001367721.1:c.2668T>G`, `NM_001410745.1:c.2650T>G`, `NM_003688.4:c.2653T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9645)
- REVEL 0.758 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.517 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.203, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.2**. 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.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (41,520,423–41,542,723), spanning 22,300 bp. Chi-square p 7.7e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00351%** (afr) · FAF95 0.000583% · FAF99 0.000218% · 2/56,922 in the highest group · 2/1,202,091 alleles overall — very rare (popmax 0.00351%, afr).

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-11.

**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 | 2025-10-11 |

## 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.

### 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 1919556). 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.*