Is CASK p.Tyr282Ter (c.846C>G) pathogenic?

CASK p.Tyr282Ter (c.846C>G) is classified Pathogenic in CASK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-03-26). Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Tyr282Ter (c.846C>G)?

CASK p.Tyr282Ter (c.846C>G) is associated with syndromic X-linked intellectual disability Najm type, FG syndrome 4, anemia, nonspherocytic hemolytic, due to G6PD deficiency (ClinVar).

How common is CASK p.Tyr282Ter (c.846C>G) in the general population?

CASK p.Tyr282Ter (c.846C>G) is absent from gnomAD v4.1 (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CASK p.Tyr282Ter

c.846C>G · rs886128077 · VCV434588

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

syndromic X-linked intellectual disability Najm type

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 9 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.59, phastCons 1
Overall
CADD	34.0	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.Tyr282Ter
Coding: c.846C>G
MANE Select: NM_001367721
dbSNP: rs886128077
Type: single nucleotide variant
Location: chrX:41636647 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 282: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix

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

Disease context

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: FG syndrome 4 anemia, nonspherocytic hemolytic, due to G6PD deficiency

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK p.Tyr282= Likely benign ★★ same residue
CASK c.1015+1G>A Pathogenic ★★ same condition
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg106Ter 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-tyr282ter (accessed [today's date]).

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