Is CASK p.Gln840Ter (c.2518C>T) pathogenic?

CASK p.Gln840Ter (c.2518C>T) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-27). Absent from gnomAD v4.1; Associated with CASK-related disorder.

What condition is associated with CASK p.Gln840Ter (c.2518C>T)?

CASK p.Gln840Ter (c.2518C>T) is associated with CASK-related disorder (ClinVar).

How common is CASK p.Gln840Ter (c.2518C>T) in the general population?

CASK p.Gln840Ter (c.2518C>T) is absent from gnomAD v4.1 (gnomAD).

CASK p.Gln840Ter

c.2518C>T · VCV4950058

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

CASK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 25 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASK
Protein: p.Gln840Ter
Coding: c.2518C>T
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41531009 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 840: 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

CASK-related disorder

Similar variants

CASK p.Gln840His Uncertain significance ★ ⚠ same residue
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Trp Pathogenic/Likely pathogenic ★★ same condition
CASK p.Gln494Ter Pathogenic/Likely pathogenic ★★ same condition
CASK c.1668+5G>A Likely pathogenic ★ same condition
CASK c.1737+2T>A Pathogenic ★ same condition
CASK c.708+2T>G Pathogenic ★ same condition
CASK c.709-1G>A Likely pathogenic ★ 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-gln840ter (accessed [today's date]).

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