Is CASK c.1233+8A>G pathogenic?

CASK c.1233+8A>G is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00142%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK c.1233+8A>G?

CASK c.1233+8A>G is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK c.1233+8A>G in the general population?

CASK c.1233+8A>G is very rare (popmax 0.00142%, nfe) (gnomAD).

CASK c.1233+8A>G

rs1412949036 · VCV2969236

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00142%, nfe)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -0.85, phastCons 0.15
Non-coding constraint	—	not assessed · autosomes only, so chrX has no window · absence ≠ unconstrained
Overall
CADD	5.569	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00142% European (non-Finnish) · 12/842,592 alleles

Filtering AF 0.000759% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0006%

Overall 0.00104% 12/1,151,856 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASK
Coding: c.1233+8A>G
MANE Select: NM_001367721
dbSNP: rs1412949036
Type: single nucleotide variant
Location: chrX:41589507 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB

Full CASK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala359Val Uncertain significance ★★ ⚠ same condition
CASK p.Ala833Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg130Cys Uncertain significance ★★ ⚠ same condition
CASK p.Arg572His Uncertain significance ★★ ⚠ same condition
CASK p.Arg61Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asp424Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp445Asn Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cask-c-1233-plus-8a-g (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown