Is CASK p.Leu820fs (c.2451_2458dup) pathogenic?

CASK p.Leu820fs (c.24512458dup) is classified Pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu820fs (c.2451_2458dup)?

CASK p.Leu820fs (c.2451_2458dup) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

CASK p.Leu820fs

c.2451_2458dup · VCV4728952

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 25 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CASK
Protein: p.Leu820fs
Coding: c.2451_2458dup
MANE Select: NM_001367721
Type: Duplication
Location: chrX:41531068 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 820: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region; an α-helix

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 c.1504-6dup Benign/Likely benign ★★ same condition
CASK c.1806+17dup Likely benign ★★ same condition
CASK p.Gln553fs Pathogenic ★ same condition
CASK p.Lys277Ter Pathogenic ★ same condition
CASK p.Val11fs Pathogenic ★ same condition
CASK c.1155+2dup Uncertain significance ★ same condition
CASK c.1669-6dup Conflicting classifications of pathogenicity ★ same condition
CASK c.1234-3dup Benign ★ 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-p-leu820fs (accessed [today's date]).

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